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Application of In Silico Techniques in Drug Design
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Application of In Silico Techniques in Drug Design

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biophysics".

Deadline for manuscript submissions: closed (20 April 2022) | Viewed by 69380

Special Issue Editor

Dr. Sugunadevi Sakkiah

E-Mail Website
Guest Editor
US Food & Drug Administration (FDA), Natl Ctr Toxicol Res, Jefferson, AR, USA
Interests: cheminformatics; computational chemistry; computer-aided drug design; machine learning; molecular docking; molecular dynamics simulations; pharmacophore modeling; predictive modeling; QSAR; structure and ligand-based pharmacophore modeling

Special Issue Information

Dear Colleagues,

At present, in silico techniques play an important role in the drug discovery process. Various computational methods are used to identify novel and potent drug candidates as well as promising targets in various diseases. Applying in silico techniques such as high-throughput virtual screening, pharmacophore screening, molecular docking, and predictive models will help to identify potent drug candidates from large databases. Predictive models using machine learning, 3D-QSAR, combination of QSAR and molecular dynamics simulations, etc. will help to predict the activity of chemicals and suggest modifying the chemical probe to enhance the chemical activity. Understanding the 3D structure of the protein and its interactions with small molecules or macromolecules is important to identify novel chemicals as a drug. Molecular docking and molecular dynamics simulation play a major role in structure-based drug design approaches. If the 3D structure of the protein is unknown, homology modeling will be employed to build 3D structures based on its amino acid sequences. Quantum and molecular mechanism can be employed to understand the mechanism of the protein–ligand complex or macromolecule complexes, which helps to give a better understanding of the biological pathways and mechanisms. All these in silico techniques will help researchers in various fields to reduce the time and cost as well as the number of animals tested in in vivo studies.

The main feature of this Special Issue is to share, in open-source format, significant works using in silico methods in drug design that can help to design or identify a novel and potent candidate drug as well as to understand the mechanism of various proteins involved in various diseases. In this Special Issue, we welcome manuscripts from researchers using any in silico techniques in original research papers, short communications, and reviews.

Dr. Sugunadevi Sakkiah
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • computational chemistry
  • computer-aided drug design
  • drug designing
  • drug discovery
  • drug repurposing
  • flexible docking
  • homology modeling
  • molecular docking
  • molecular dynamics simulation
  • molecular modeling
  • predictive models using machine learning or deep learning or AI
  • QSAR
  • structure and ligand-based pharmacophore model
  • virtual screening

Published Papers (20 papers)

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30 pages, 7872 KiB  
Article
Identification of Potential Insect Growth Inhibitor against Aedes aegypti: A Bioinformatics Approach
by Glauber V. Da Costa, Moysés F. A. Neto, Alicia K. P. Da Silva, Ester M. F. De Sá, Luanne C. F. Cancela, Jeanina S. Vega, Cássio M. Lobato, Juliana P. Zuliani, José M. Espejo-Román, Joaquín M. Campos, Franco H. A. Leite and Cleydson B. R. Santos
Int. J. Mol. Sci. 2022, 23(15), 8218; https://doi.org/10.3390/ijms23158218 - 26 Jul 2022
Cited by 3 | Viewed by 2833
Abstract
Aedes aegypti is the main vector that transmits viral diseases such as dengue, hemorrhagic dengue, urban yellow fever, zika, and chikungunya. Worldwide, many cases of dengue have been reported in recent years, showing significant growth. The best way to manage diseases transmitted by [...] Read more.
Aedes aegypti is the main vector that transmits viral diseases such as dengue, hemorrhagic dengue, urban yellow fever, zika, and chikungunya. Worldwide, many cases of dengue have been reported in recent years, showing significant growth. The best way to manage diseases transmitted by Aedes aegypti is to control the vector with insecticides, which have already been shown to be toxic to humans; moreover, insects have developed resistance. Thus, the development of new insecticides is considered an emergency. One way to achieve this goal is to apply computational methods based on ligands and target information. In this study, sixteen compounds with acceptable insecticidal activities, with 100% larvicidal activity at low concentrations (2.0 to 0.001 mg·L−1), were selected from the literature. These compounds were used to build up and validate pharmacophore models. Pharmacophore model 6 (AUC = 0.78; BEDROC = 0.6) was used to filter 4793 compounds from the subset of lead-like compounds from the ZINC database; 4142 compounds (dG < 0 kcal/mol) were then aligned to the active site of the juvenile hormone receptor Aedes aegypti (PDB: 5V13), 2240 compounds (LE < −0.40 kcal/mol) were prioritized for molecular docking from the construction of a chitin deacetylase model of Aedes aegypti by the homology modeling of the Bombyx mori species (PDB: 5ZNT), which aligned 1959 compounds (dG < 0 kcal/mol), and 20 compounds (LE < −0.4 kcal/mol) were predicted for pharmacokinetic and toxicological prediction in silico (Preadmet, SwissADMET, and eMolTox programs). Finally, the theoretical routes of compounds M01, M02, M03, M04, and M05 were proposed. Compounds M01–M05 were selected, showing significant differences in pharmacokinetic and toxicological parameters in relation to positive controls and interaction with catalytic residues among key protein sites reported in the literature. For this reason, the molecules investigated here are dual inhibitors of the enzymes chitin synthase and juvenile hormonal protein from insects and humans, characterizing them as potential insecticides against the Aedes aegypti mosquito. Full article
(This article belongs to the Special Issue Application of In Silico Techniques in Drug Design)
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17 pages, 3956 KiB  
Article
A Novel Synthetic Antibody Library with Complementarity-Determining Region Diversities Designed for an Improved Amplification Profile
by Xuelian Bai, Moonseon Jang, Nam Ju Lee, Thi Thu Ha Nguyen, Mooyoung Jung, Jeong Yeon Hwang and Hyunbo Shim
Int. J. Mol. Sci. 2022, 23(11), 6255; https://doi.org/10.3390/ijms23116255 - 2 Jun 2022
Cited by 2 | Viewed by 2561
Abstract
Antibody discovery by phage display consists of two phases, i.e., the binding phase and the amplification phase. Ideally, the selection process is dominated by the former, and all the retrieved clones are amplified equally during the latter. In reality, the amplification efficiency of [...] Read more.
Antibody discovery by phage display consists of two phases, i.e., the binding phase and the amplification phase. Ideally, the selection process is dominated by the former, and all the retrieved clones are amplified equally during the latter. In reality, the amplification efficiency of antibody fragments varies widely among different sequences and, after a few rounds of phage display panning, the output repertoire often includes rapidly amplified sequences with low or no binding activity, significantly diminishing the efficiency of antibody isolation. In this work, a novel synthetic single-chain variable fragment (scFv) library with complementarity-determining region (CDR) diversities aimed at improved amplification efficiency was designed and constructed. A previously reported synthetic scFv library with low, non-combinatorial CDR diversities was panned against protein A superantigen, and the library repertoires before and after the panning were analyzed by next generation sequencing. The enrichment or depletion patterns of CDR sequences after panning served as the basis for the design of the new library. Especially for CDR-H3 with a higher and more random diversity, a machine learning method was applied to predict potential fast-amplified sequences among a simulated sequence repertoire. In a direct comparison with the previous generation library, the new library performed better against a panel of antigens in terms of the number of binders isolated, the number of unique sequences, and/or the speed of binder enrichment. Our results suggest that the amplification-centric design of sequence diversity is a valid strategy for the construction of highly functional phage display antibody libraries. Full article
(This article belongs to the Special Issue Application of In Silico Techniques in Drug Design)
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15 pages, 4279 KiB  
Article
Comparative Analyses of Medicinal Chemistry and Cheminformatics Filters with Accessible Implementation in Konstanz Information Miner (KNIME)
by Sebastjan Kralj, Marko Jukič and Urban Bren
Int. J. Mol. Sci. 2022, 23(10), 5727; https://doi.org/10.3390/ijms23105727 - 20 May 2022
Cited by 11 | Viewed by 2975
Abstract
High-throughput virtual screening (HTVS) is, in conjunction with rapid advances in computer hardware, becoming a staple in drug design research campaigns and cheminformatics. In this context, virtual compound library design becomes crucial as it generally constitutes the first step where quality filtered databases [...] Read more.
High-throughput virtual screening (HTVS) is, in conjunction with rapid advances in computer hardware, becoming a staple in drug design research campaigns and cheminformatics. In this context, virtual compound library design becomes crucial as it generally constitutes the first step where quality filtered databases are essential for the efficient downstream research. Therefore, multiple filters for compound library design were devised and reported in the scientific literature. We collected the most common filters in medicinal chemistry (PAINS, REOS, Aggregators, van de Waterbeemd, Oprea, Fichert, Ghose, Mozzicconacci, Muegge, Egan, Murcko, Veber, Ro3, Ro4, and Ro5) to facilitate their open access use and compared them. Then, we implemented these filters in the open platform Konstanz Information Miner (KNIME) as a freely accessible and simple workflow compatible with small or large compound databases for the benefit of the readers and for the help in the early drug design steps. Full article
(This article belongs to the Special Issue Application of In Silico Techniques in Drug Design)
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27 pages, 3365 KiB  
Article
The Distribution of Glucosinolates in Different Phenotypes of Lepidium peruvianum and Their Role as Acetyl- and Butyrylcholinesterase Inhibitors—In Silico and In Vitro Studies
by Dominik Tarabasz, Paweł Szczeblewski, Tomasz Laskowski, Wojciech Płaziński, Ewa Baranowska-Wójcik, Dominik Szwajgier, Wirginia Kukula-Koch and Henry O. Meissner
Int. J. Mol. Sci. 2022, 23(9), 4858; https://doi.org/10.3390/ijms23094858 - 27 Apr 2022
Cited by 9 | Viewed by 2267
Abstract
The aim of the study was to present the fingerprint of different Lepidium peruvianum tuber extracts showing glucosinolates-containing substances possibly playing an important role in preventinting dementia and other memory disorders. Different phenotypes of Lepidium peruvianum (Brassicaceae) tubers were analysed for their glucosinolate [...] Read more.
The aim of the study was to present the fingerprint of different Lepidium peruvianum tuber extracts showing glucosinolates-containing substances possibly playing an important role in preventinting dementia and other memory disorders. Different phenotypes of Lepidium peruvianum (Brassicaceae) tubers were analysed for their glucosinolate profile using a liquid chromatograph coupled with mass spectrometer (HPLC-ESI-QTOF-MS/MS platform). Qualitative analysis in 50% ethanolic extracts confirmed the presence of ten compounds: aliphatic, indolyl, and aromatic glucosinolates, with glucotropaeolin being the leading one, detected at levels between 0–1.57% depending on phenotype, size, processing, and collection site. The PCA analysis showed important variations in glucosinolate content between the samples and different ratios of the detected compounds. Applied in vitro activity tests confirmed inhibitory properties of extracts and single glucosinolates against acetylcholinesterase (AChE) (15.3–28.9% for the extracts and 55.95–57.60% for individual compounds) and butyrylcholinesterase (BuChE) (71.3–77.2% for the extracts and 36.2–39.9% for individual compounds). The molecular basis for the activity of glucosinolates was explained through molecular docking studies showing that the tested metabolites interacted with tryptophan and histidine residues of the enzymes, most likely blocking their active catalytic side. Based on the obtained results and described mechanism of action, it could be concluded that glucosinolates exhibit inhibitory properties against two cholinesterases present in the synaptic cleft, which indicates that selected phenotypes of L. peruvianum tubers cultivated under well-defined environmental and ecological conditions may present a valuable plant material to be considered for the development of therapeutic products with memory-stimulating properties. Full article
(This article belongs to the Special Issue Application of In Silico Techniques in Drug Design)
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21 pages, 4184 KiB  
Article
In Silico Drug Repositioning to Target the SARS-CoV-2 Main Protease as Covalent Inhibitors Employing a Combined Structure-Based Virtual Screening Strategy of Pharmacophore Models and Covalent Docking
by Luis Heriberto Vázquez-Mendoza, Humberto L. Mendoza-Figueroa, Juan Benjamín García-Vázquez, José Correa-Basurto and Jazmín García-Machorro
Int. J. Mol. Sci. 2022, 23(7), 3987; https://doi.org/10.3390/ijms23073987 - 3 Apr 2022
Cited by 5 | Viewed by 3430
Abstract
The epidemic caused by the SARS-CoV-2 coronavirus, which has spread rapidly throughout the world, requires urgent and effective treatments considering that the appearance of viral variants limits the efficacy of vaccines. The main protease of SARS-CoV-2 (Mpro) is a highly conserved [...] Read more.
The epidemic caused by the SARS-CoV-2 coronavirus, which has spread rapidly throughout the world, requires urgent and effective treatments considering that the appearance of viral variants limits the efficacy of vaccines. The main protease of SARS-CoV-2 (Mpro) is a highly conserved cysteine proteinase, fundamental for the replication of the coronavirus and with a specific cleavage mechanism that positions it as an attractive therapeutic target for the proposal of irreversible inhibitors. A structure-based strategy combining 3D pharmacophoric modeling, virtual screening, and covalent docking was employed to identify the interactions required for molecular recognition, as well as the spatial orientation of the electrophilic warhead, of various drugs, to achieve a covalent interaction with Cys145 of Mpro. The virtual screening on the structure-based pharmacophoric map of the SARS-CoV-2 Mpro in complex with an inhibitor N3 (reference compound) provided high efficiency by identifying 53 drugs (FDA and DrugBank databases) with probabilities of covalent binding, including N3 (Michael acceptor) and others with a variety of electrophilic warheads. Adding the energy contributions of affinity for non-covalent and covalent docking, 16 promising drugs were obtained. Our findings suggest that the FDA-approved drugs Vaborbactam, Cimetidine, Ixazomib, Scopolamine, and Bicalutamide, as well as the other investigational peptide-like drugs (DB04234, DB03456, DB07224, DB7252, and CMX-2043) are potential covalent inhibitors of SARS-CoV-2 Mpro. Full article
(This article belongs to the Special Issue Application of In Silico Techniques in Drug Design)
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19 pages, 5787 KiB  
Article
Identification of New KRAS G12D Inhibitors through Computer-Aided Drug Discovery Methods
by Apoorva M. Kulkarni, Vikas Kumar, Shraddha Parate, Gihwan Lee, Sanghwa Yoon and Keun Woo Lee
Int. J. Mol. Sci. 2022, 23(3), 1309; https://doi.org/10.3390/ijms23031309 - 24 Jan 2022
Cited by 14 | Viewed by 5130
Abstract
Owing to several mutations, the oncogene Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) is activated in the majority of cancers, and targeting it has been pharmacologically challenging. In this study, using an in silico approach comprised of pharmacophore modeling, molecular docking, and [...] Read more.
Owing to several mutations, the oncogene Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) is activated in the majority of cancers, and targeting it has been pharmacologically challenging. In this study, using an in silico approach comprised of pharmacophore modeling, molecular docking, and molecular dynamics simulations, potential KRAS G12D inhibitors were investigated. A ligand-based common feature pharmacophore model was generated to identify the framework necessary for effective KRAS inhibition. The chemical features in the selected pharmacophore model comprised two hydrogen bond donors, one hydrogen bond acceptor, two aromatic rings and one hydrophobic feature. This model was used for screening in excess of 214,000 compounds from InterBioScreen (IBS) and ZINC databases. Eighteen compounds from the IBS and ten from the ZINC database mapped onto the pharmacophore model and were subjected to molecular docking. Molecular docking results highlighted a higher affinity of four hit compounds towards KRAS G12D in comparison to the reference inhibitor, BI-2852. Sequential molecular dynamics (MD) simulation studies revealed all four hit compounds them possess higher KRAS G12D binding free energy and demonstrate stable polar interaction with key residues. Further, Principal Component Analysis (PCA) analysis of the hit compounds in complex with KRAS G12D also indicated stability. Overall, the research undertaken provides strong support for further in vitro testing of these newly identified KRAS G12D inhibitors, particularly Hit1 and Hit2. Full article
(This article belongs to the Special Issue Application of In Silico Techniques in Drug Design)
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17 pages, 6148 KiB  
Article
Identification of a Novel Theranostic Signature of Metabolic and Immune-Inflammatory Dysregulation in Myocardial Infarction, and the Potential Therapeutic Properties of Ovatodiolide, a Diterpenoid Derivative
by Alexander T. H. Wu, Bashir Lawal, Yew-Min Tzeng, Chun-Che Shih and Chun-Ming Shih
Int. J. Mol. Sci. 2022, 23(3), 1281; https://doi.org/10.3390/ijms23031281 - 24 Jan 2022
Cited by 11 | Viewed by 2859
Abstract
Myocardial infarction (MI) is a multifactorial global disease, recognized as one of the leading causes of cardiovascular morbidity and mortality. Timely and correct diagnoses and effective treatments could significantly reduce incidence of complications and improve patient prognoses. In this study, seven unconventional differentially [...] Read more.
Myocardial infarction (MI) is a multifactorial global disease, recognized as one of the leading causes of cardiovascular morbidity and mortality. Timely and correct diagnoses and effective treatments could significantly reduce incidence of complications and improve patient prognoses. In this study, seven unconventional differentially expressed genes (DEGs) (MAN2A2, TNFRSF12A, SPP1, CSNK1D, PLAUR, PFKFB3, and CXCL16, collectively termed the MTSCPPC signature) were identified through integrating DEGs from six MI microarray datasets. The pathological and theranostic roles of the MTSCPPC signature in MI were subsequently analyzed. We evaluated interactions of the MTSCPPC signature with ovatodiolide, a bioactive compound isolated from Anisomeles indica (L.) Kuntze, using in silico molecular docking tools and compared it to specific inhibitors of the members of the MTSCPPC signature. Single-cell transcriptomic analysis of the public databases revealed high expression levels of the MTSCPPC signature in immune cells of adult human hearts during an MI event. The MTSCPPC signature was significantly associated with the cytokine–cytokine receptor interactions, chemokine signaling, immune and inflammatory responses, and metabolic dysregulation in MI. Analysis of a micro (mi)RNA regulatory network of the MTSCPPC signature suggested post-transcriptional activation and the roles of miRNAs in the pathology of MI. Our molecular docking analysis suggested a higher potential for ovatodiolide to target MAN2A2, CSNK1D, and TNFRSF12A. Collectively, the results derived from the present study further advance our understanding of the complex regulatory mechanisms of MI and provide a potential MI theranostic signature with ovatodiolide as a therapeutic candidate. Full article
(This article belongs to the Special Issue Application of In Silico Techniques in Drug Design)
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18 pages, 3042 KiB  
Article
Antifungal Activity of N-(4-Halobenzyl)amides against Candida spp. and Molecular Modeling Studies
by Yunierkis Perez-Castillo, Ricardo Carneiro Montes, Cecília Rocha da Silva, João Batista de Andrade Neto, Celidarque da Silva Dias, Allana Brunna Sucupira Duarte, Hélio Vitoriano Nobre Júnior and Damião Pergentino de Sousa
Int. J. Mol. Sci. 2022, 23(1), 419; https://doi.org/10.3390/ijms23010419 - 31 Dec 2021
Cited by 9 | Viewed by 2073
Abstract
Fungal infections remain a high-incidence worldwide health problem that is aggravated by limited therapeutic options and the emergence of drug-resistant strains. Cinnamic and benzoic acid amides have previously shown bioactivity against different species belonging to the Candida genus. Here, 20 cinnamic and benzoic [...] Read more.
Fungal infections remain a high-incidence worldwide health problem that is aggravated by limited therapeutic options and the emergence of drug-resistant strains. Cinnamic and benzoic acid amides have previously shown bioactivity against different species belonging to the Candida genus. Here, 20 cinnamic and benzoic acid amides were synthesized and tested for inhibition of C. krusei ATCC 14243 and C. parapsilosis ATCC 22019. Five compounds inhibited the Candida strains tested, with compound 16 (MIC = 7.8 µg/mL) producing stronger antifungal activity than fluconazole (MIC = 16 µg/mL) against C. krusei ATCC 14243. It was also tested against eight Candida strains, including five clinical strains resistant to fluconazole, and showed an inhibitory effect against all strains tested (MIC = 85.3–341.3 µg/mL). The MIC value against C. krusei ATCC 6258 was 85.3 mcg/mL, while against C. krusei ATCC 14243, it was 10.9 times smaller. This strain had greater sensitivity to the antifungal action of compound 16. The inhibition of C. krusei ATCC 14243 and C. parapsilosis ATCC 22019 was also achieved by compounds 2, 9, 12, 14 and 15. Computational experiments combining target fishing, molecular docking and molecular dynamics simulations were performed to study the potential mechanism of action of compound 16 against C. krusei. From these, a multi-target mechanism of action is proposed for this compound that involves proteins related to critical cellular processes such as the redox balance, kinases-mediated signaling, protein folding and cell wall synthesis. The modeling results might guide future experiments focusing on the wet-lab investigation of the mechanism of action of this series of compounds, as well as on the optimization of their inhibitory potency. Full article
(This article belongs to the Special Issue Application of In Silico Techniques in Drug Design)
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15 pages, 1966 KiB  
Article
Treatment of HT29 Human Colorectal Cancer Cell Line with Nanocarrier-Encapsulated Camptothecin Reveals Histone Modifier Genes in the Wnt Signaling Pathway as Important Molecular Cues for Colon Cancer Targeting
by Aisha Farhana, Avin Ee-Hwan Koh, Sangeetha Kothandan, Abdullah Alsrhani, Pooi Ling Mok and Suresh Kumar Subbiah
Int. J. Mol. Sci. 2021, 22(22), 12286; https://doi.org/10.3390/ijms222212286 - 13 Nov 2021
Cited by 4 | Viewed by 2697
Abstract
Cancer cells are able to proliferate in an unregulated manner. There are several mechanisms involved that propel such neoplastic transformations. One of these processes involves bypassing cell death through changes in gene expression and, consequently, cell growth. This involves a complex epigenetic interaction [...] Read more.
Cancer cells are able to proliferate in an unregulated manner. There are several mechanisms involved that propel such neoplastic transformations. One of these processes involves bypassing cell death through changes in gene expression and, consequently, cell growth. This involves a complex epigenetic interaction within the cell, which drives it towards oncogenic transformations. These epigenetic events augment cellular growth by potentially altering chromatin structures and influencing key gene expressions. Therapeutic mechanisms have been developed to combat this by taking advantage of the underlying oncogenic mechanisms through chemical modulation. Camptothecin (CPT) is an example of this type of drug. It is a selective topoisomerase I inhibitor that is effective against many cancers, such as colorectal cancer. Previously, we successfully formulated a magnetic nanocarrier-conjugated CPT with β-cyclodextrin and iron NPs (Fe3O4) cross-linked using EDTA (CPT-CEF). Compared to CPT alone, it boasts higher efficacy due to its selective targeting and increased solubility. In this study, we treated HT29 colon cancer cells with CPT-CEF and attempted to investigate the cytotoxic effects of the formulation through an epigenetic perspective. By using RNA-Seq, several differentially expressed genes were obtained (p < 0.05). Enrichr was then used for the over-representation analysis, and the genes were compared to the epigenetic roadmap and histone modification database. The results showed that the DEGs had a high correlation with epigenetic modifications involving histone H3 acetylation. Furthermore, a subset of these genes was shown to be associated with the Wnt/β-catenin signaling pathway, which is highly upregulated in a large number of cancer cells. These genes could be investigated as downstream therapeutic targets against the uncontrolled proliferation of cancer cells. Further interaction analysis of the identified genes with the key genes of the Wnt/β-catenin signaling pathway in colorectal cancer identified the direct interactors and a few transcription regulators. Further analysis in cBioPortal confirmed their genetic alterations and their distribution across patient samples. Thus, the findings of this study reveal that colorectal cancer could be reversed by treatment with the CPT-CEF nanoparticle-conjugated nanocarrier through an epigenetic mechanism. Full article
(This article belongs to the Special Issue Application of In Silico Techniques in Drug Design)
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18 pages, 4780 KiB  
Article
Elucidation of Agonist and Antagonist Dynamic Binding Patterns in ER-α by Integration of Molecular Docking, Molecular Dynamics Simulations and Quantum Mechanical Calculations
by Sugunadevi Sakkiah, Chandrabose Selvaraj, Wenjing Guo, Jie Liu, Weigong Ge, Tucker A. Patterson and Huixiao Hong
Int. J. Mol. Sci. 2021, 22(17), 9371; https://doi.org/10.3390/ijms22179371 - 29 Aug 2021
Cited by 9 | Viewed by 3040
Abstract
Estrogen receptor alpha (ERα) is a ligand-dependent transcriptional factor in the nuclear receptor superfamily. Many structures of ERα bound with agonists and antagonists have been determined. However, the dynamic binding patterns of agonists and antagonists in the binding site of ERα remains unclear. [...] Read more.
Estrogen receptor alpha (ERα) is a ligand-dependent transcriptional factor in the nuclear receptor superfamily. Many structures of ERα bound with agonists and antagonists have been determined. However, the dynamic binding patterns of agonists and antagonists in the binding site of ERα remains unclear. Therefore, we performed molecular docking, molecular dynamics (MD) simulations, and quantum mechanical calculations to elucidate agonist and antagonist dynamic binding patterns in ERα. 17β-estradiol (E2) and 4-hydroxytamoxifen (OHT) were docked in the ligand binding pockets of the agonist and antagonist bound ERα. The best complex conformations from molecular docking were subjected to 100 nanosecond MD simulations. Hierarchical clustering was conducted to group the structures in the trajectory from MD simulations. The representative structure from each cluster was selected to calculate the binding interaction energy value for elucidation of the dynamic binding patterns of agonists and antagonists in the binding site of ERα. The binding interaction energy analysis revealed that OHT binds ERα more tightly in the antagonist conformer, while E2 prefers the agonist conformer. The results may help identify ERα antagonists as drug candidates and facilitate risk assessment of chemicals through ER-mediated responses. Full article
(This article belongs to the Special Issue Application of In Silico Techniques in Drug Design)
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12 pages, 863 KiB  
Article
Structure-Activity Relationships of the Imidazolium Compounds as Antibacterials of Staphylococcus aureus and Pseudomonas aeruginosa
by Łukasz Pałkowski, Maciej Karolak, Jerzy Błaszczyński, Jerzy Krysiński and Roman Słowiński
Int. J. Mol. Sci. 2021, 22(15), 7997; https://doi.org/10.3390/ijms22157997 - 27 Jul 2021
Cited by 4 | Viewed by 1631
Abstract
This paper presents the results of structure–activity relationship (SAR) studies of 140 3,3’-(α,ω-dioxaalkan)bis(1-alkylimidazolium) chlorides. In the SAR analysis, the dominance-based rough set approach (DRSA) was used. For analyzed compounds, minimum inhibitory concentration (MIC) against strains of Staphylococcus aureus and Pseudomonas aeruginosa was determined. [...] Read more.
This paper presents the results of structure–activity relationship (SAR) studies of 140 3,3’-(α,ω-dioxaalkan)bis(1-alkylimidazolium) chlorides. In the SAR analysis, the dominance-based rough set approach (DRSA) was used. For analyzed compounds, minimum inhibitory concentration (MIC) against strains of Staphylococcus aureus and Pseudomonas aeruginosa was determined. In order to perform the SAR analysis, a tabular information system was formed, in which tested compounds were described by means of condition attributes, characterizing the structure (substructure parameters and molecular descriptors) and their surface properties, and a decision attribute, classifying compounds with respect to values of MIC. DRSA allows to induce decision rules from data describing the compounds in terms of condition and decision attributes, and to rank condition attributes with respect to relevance using a Bayesian confirmation measure. Decision rules present the most important relationships between structure and surface properties of the compounds on one hand, and their antibacterial activity on the other hand. They also indicate directions of synthesizing more efficient antibacterial compounds. Moreover, the analysis showed differences in the application of various parameters for Gram-positive and Gram-negative strains, respectively. Full article
(This article belongs to the Special Issue Application of In Silico Techniques in Drug Design)
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21 pages, 5193 KiB  
Article
Identification of a Chitooligosaccharide Mechanism against Bacterial Leaf Blight on Rice by In Vitro and In Silico Studies
by Supatcharee Siriwong, Wannaporn Thepbandit, Nguyen Huy Hoang, Narendra Kumar Papathoti, Karsidete Teeranitayatarn, Tippawun Saardngen, Kanjana Thumanu, Sundaresan Bhavaniramya, Vaseeharan Baskaralingam, Toan Le Thanh, Piyaporn Phansak and Natthiya Buensanteai
Int. J. Mol. Sci. 2021, 22(15), 7990; https://doi.org/10.3390/ijms22157990 - 27 Jul 2021
Cited by 8 | Viewed by 2798
Abstract
This study focuses on a commercial plant elicitor based on chitooligosaccharides (BIG®), which aids in rice plant growth and disease resistance to bacterial leaf blight (BLB). When the pathogen (Xoo) vigorously attacks rice that has suffered yield losses, it [...] Read more.
This study focuses on a commercial plant elicitor based on chitooligosaccharides (BIG®), which aids in rice plant growth and disease resistance to bacterial leaf blight (BLB). When the pathogen (Xoo) vigorously attacks rice that has suffered yield losses, it can cause damage in up to 20% of the plant. Furthermore, Xoo is a seed-borne pathogen that can survive in rice seeds for an extended period. In this study, when rice seeds were soaked and sprayed with BIG®, there was a significant increase in shoot and root length, as well as plant biomass. Furthermore, BIG®-treated rice plants showed a significant reduction in BLB severity of more than 33%. Synchrotron radiation-based Fourier transform infrared (SR-FTIR) analysis was used to characterize BIG®’s mechanism in the chemical structure of rice leaves. The SR-FTIR results at 1650, 1735, and 1114 cm−1 indicated changes in biochemical components such as pectins, lignins, proteins, and celluloses. These findings demonstrated that commercial BIG® not only increased rice growth but also induced resistance to BLB. The drug’s target enzyme, Xoo 1075 from Xanthomonas oryzae (PDB ID: 5CY8), was analyzed for its interactions with polymer ingredients, specifically chitooligosaccharides, to gain molecular insights down to the atomic level. The results are intriguing, with a strong binding of the chitooligosaccharide polymer with the drug target, revealing 10 hydrogen bonds between the protein and polymer. Overall, the computational analysis supported the experimentally demonstrated strong binding of chitooligosaccharides to the drug target. Full article
(This article belongs to the Special Issue Application of In Silico Techniques in Drug Design)
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16 pages, 3018 KiB  
Article
Simulations of Promising Indolizidine—α6-β2 Nicotinic Acetylcholine Receptor Complexes
by Francis A. Acquah, Matthew Paramel, Adama Kuta, Syed R. Hussaini, David R. Wallace and Blaine H. M. Mooers
Int. J. Mol. Sci. 2021, 22(15), 7934; https://doi.org/10.3390/ijms22157934 - 25 Jul 2021
Cited by 1 | Viewed by 4973
Abstract
Smoking-cessation drugs bind many off-target nicotinic acetylcholine receptors (nAChRs) and cause severe side effects if they are based on nicotine. New drugs that bind only those receptors, such as α6β2* nAChR, implicated in nicotine addiction would avoid the off-target binding. [...] Read more.
Smoking-cessation drugs bind many off-target nicotinic acetylcholine receptors (nAChRs) and cause severe side effects if they are based on nicotine. New drugs that bind only those receptors, such as α6β2* nAChR, implicated in nicotine addiction would avoid the off-target binding. Indolizidine (-)-237D (IND (-)-237D), a bicyclic alkaloid, has been shown to block α6β2* containing nAChRs and functionally inhibit the nicotine-evoked dopamine release. To improve the affinity of indolizidine (-)-237D for α6β2*, we built a library of 2226 analogs. We screened virtually the library against a homology model of α6β2 nAChR that we derived from the recent crystal structure of α4β2 nAChR. We also screened the crystal structure of α4β2 nAChR as a control on specificity. We ranked the compounds based on their predicted free energy of binding. We selected the top eight compounds bound in their best pose and subjected the complexes to 100 ns molecular dynamics simulations to assess the stability of the complexes. All eight analogs formed stable complexes for the duration of the simulations. The results from this work highlight nine distinct analogs of IND (-)-237D with high affinity towards α6β2* nAChR. These leads can be synthesized and tested in in vitro and in vivo studies as lead candidates for drugs to treat nicotine addiction. Full article
(This article belongs to the Special Issue Application of In Silico Techniques in Drug Design)
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16 pages, 6479 KiB  
Article
Towards Novel 3-Aminopyrazinamide-Based Prolyl-tRNA Synthetase Inhibitors: In Silico Modelling, Thermal Shift Assay and Structural Studies
by Luping Pang, Stephen D. Weeks, Martin Juhás, Sergei V. Strelkov, Jan Zitko and Arthur Van Aerschot
Int. J. Mol. Sci. 2021, 22(15), 7793; https://doi.org/10.3390/ijms22157793 - 21 Jul 2021
Cited by 6 | Viewed by 2679
Abstract
Human cytosolic prolyl-tRNA synthetase (HcProRS) catalyses the formation of the prolyl-tRNAPro, playing an important role in protein synthesis. Inhibition of HcProRS activity has been shown to have potential benefits in the treatment of fibrosis, autoimmune diseases and cancer. Recently, potent pyrazinamide-based [...] Read more.
Human cytosolic prolyl-tRNA synthetase (HcProRS) catalyses the formation of the prolyl-tRNAPro, playing an important role in protein synthesis. Inhibition of HcProRS activity has been shown to have potential benefits in the treatment of fibrosis, autoimmune diseases and cancer. Recently, potent pyrazinamide-based inhibitors were identified by a high-throughput screening (HTS) method, but no further elaboration was reported. The pyrazinamide core is a bioactive fragment found in numerous clinically validated drugs and has been subjected to various modifications. Therefore, we applied a virtual screening protocol to our in-house library of pyrazinamide-containing small molecules, searching for potential novel HcProRS inhibitors. We identified a series of 3-benzylaminopyrazine-2-carboxamide derivatives as positive hits. Five of them were confirmed by a thermal shift assay (TSA) with the best compounds 3b and 3c showing EC50 values of 3.77 and 7.34 µM, respectively, in the presence of 1 mM of proline (Pro) and 3.45 µM enzyme concentration. Co-crystal structures of HcProRS in complex with these compounds and Pro confirmed the initial docking studies and show how the Pro facilitates binding of the ligands that compete with ATP substrate. Modelling 3b into other human class II aminoacyl-tRNA synthetases (aaRSs) indicated that the subtle differences in the ATP binding site of these enzymes likely contribute to its potential selective binding of HcProRS. Taken together, this study successfully identified novel HcProRS binders from our anti-tuberculosis in-house compound library, displaying opportunities for repurposing old drug candidates for new applications such as therapeutics in HcProRS-related diseases. Full article
(This article belongs to the Special Issue Application of In Silico Techniques in Drug Design)
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19 pages, 6589 KiB  
Article
The Structural Effect of FLT3 Mutations at 835th Position and Their Interaction with Acute Myeloid Leukemia Inhibitors: In Silico Approach
by Abeer M. Al-Subaie and Balu Kamaraj
Int. J. Mol. Sci. 2021, 22(14), 7602; https://doi.org/10.3390/ijms22147602 - 16 Jul 2021
Cited by 19 | Viewed by 3546
Abstract
FMS-like tyrosine kinase 3 (FLT3) gene mutations have been found in more than one-third of Acute Myeloid Leukemia (AML) cases. The most common point mutation in FLT3 occurs at the 835th residue (D835A/E/F/G/H/I/N/V/Y), in the activation loop region. The D835 residue is critical [...] Read more.
FMS-like tyrosine kinase 3 (FLT3) gene mutations have been found in more than one-third of Acute Myeloid Leukemia (AML) cases. The most common point mutation in FLT3 occurs at the 835th residue (D835A/E/F/G/H/I/N/V/Y), in the activation loop region. The D835 residue is critical in maintaining FLT3 inactive conformation; these mutations might influence the interaction with clinically approved AML inhibitors used to treat the AML. The molecular mechanism of each of these mutations and their interactions with AML inhibitors at the atomic level is still unknown. In this manuscript, we have investigated the structural consequence of native and mutant FLT-3 proteins and their molecular mechanisms at the atomic level, using molecular dynamics simulations (MDS). In addition, we use the molecular docking method to investigate the binding pattern between the FLT-3 protein and AML inhibitors upon mutations. This study apparently elucidates that, due to mutations in the D835, the FLT-3 structure loses its conformation and becomes more flexible compared to the native FLT3 protein. These structural changes are suggested to contribute to the relapse and resistance responses to AML inhibitors. Identifying the effects of FLT3 at the molecular level will aid in developing a personalized therapeutic strategy for treating patients with FLT-3-associated AML. Full article
(This article belongs to the Special Issue Application of In Silico Techniques in Drug Design)
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22 pages, 5569 KiB  
Article
Structure-Based Virtual Screening Reveals Ibrutinib and Zanubrutinib as Potential Repurposed Drugs against COVID-19
by Satyavani Kaliamurthi, Gurudeeban Selvaraj, Chandrabose Selvaraj, Sanjeev Kumar Singh, Dong-Qing Wei and Gilles H. Peslherbe
Int. J. Mol. Sci. 2021, 22(13), 7071; https://doi.org/10.3390/ijms22137071 - 30 Jun 2021
Cited by 20 | Viewed by 4292
Abstract
Coronavirus disease (COVID)-19 is the leading global health threat to date caused by a severe acute respiratory syndrome coronavirus (SARS-CoV-2). Recent clinical trials reported that the use of Bruton’s tyrosine kinase (BTK) inhibitors to treat COVID-19 patients could reduce dyspnea and hypoxia, thromboinflammation, [...] Read more.
Coronavirus disease (COVID)-19 is the leading global health threat to date caused by a severe acute respiratory syndrome coronavirus (SARS-CoV-2). Recent clinical trials reported that the use of Bruton’s tyrosine kinase (BTK) inhibitors to treat COVID-19 patients could reduce dyspnea and hypoxia, thromboinflammation, hypercoagulability and improve oxygenation. However, the mechanism of action remains unclear. Thus, this study employs structure-based virtual screening (SBVS) to repurpose BTK inhibitors acalabrutinib, dasatinib, evobrutinib, fostamatinib, ibrutinib, inositol 1,3,4,5-tetrakisphosphate, spebrutinib, XL418 and zanubrutinib against SARS-CoV-2. Molecular docking is conducted with BTK inhibitors against structural and nonstructural proteins of SARS-CoV-2 and host targets (ACE2, TMPRSS2 and BTK). Molecular mechanics-generalized Born surface area (MM/GBSA) calculations and molecular dynamics (MD) simulations are then carried out on the selected complexes with high binding energy. Ibrutinib and zanubrutinib are found to be the most potent of the drugs screened based on the results of computational studies. Results further show that ibrutinib and zanubrutinib could exploit different mechanisms at the viral entry and replication stage and could be repurposed as potential inhibitors of SARS-CoV-2 pathogenesis. Full article
(This article belongs to the Special Issue Application of In Silico Techniques in Drug Design)
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11 pages, 2147 KiB  
Article
Antiviral Activity of Two Marine Carotenoids against SARS-CoV-2 Virus Entry In Silico and In Vitro
by Sung-Kun Yim, Inhee Kim, Boyd Warren, Jungwon Kim, Kyoojin Jung and Bosung Ku
Int. J. Mol. Sci. 2021, 22(12), 6481; https://doi.org/10.3390/ijms22126481 - 17 Jun 2021
Cited by 20 | Viewed by 3201
Abstract
The marine carotenoids fucoxanthin and siphonaxanthin are powerful antioxidants that are attracting focused attention to identify a variety of health benefits and industry applications. In this study, the binding energy of these carotenoids with the SARS-CoV-2 Spike-glycoprotein was predicted by molecular docking simulation, [...] Read more.
The marine carotenoids fucoxanthin and siphonaxanthin are powerful antioxidants that are attracting focused attention to identify a variety of health benefits and industry applications. In this study, the binding energy of these carotenoids with the SARS-CoV-2 Spike-glycoprotein was predicted by molecular docking simulation, and their inhibitory activity was confirmed with SARS-CoV-2 pseudovirus on HEK293 cells overexpressing angiotensin-converting enzyme 2 (ACE2). Siphonaxanthin from Codium fragile showed significant antiviral activity with an IC50 of 87.4 μM against SARS-CoV-2 pseudovirus entry, while fucoxanthin from Undaria pinnatifida sporophyll did not. The acute toxicities were predicted to be relatively low, and pharmacokinetic predictions indicate GI absorption. Although further studies are needed to elucidate the inhibition of viral infection by siphonaxanthin, these results provide useful information in the application of these marine carotenoids for the treatment and prevention of COVID-19. Full article
(This article belongs to the Special Issue Application of In Silico Techniques in Drug Design)
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15 pages, 3113 KiB  
Article
Off-Target-Based Design of Selective HIV-1 PROTEASE Inhibitors
by Gabriele La Monica, Antonino Lauria, Alessia Bono and Annamaria Martorana
Int. J. Mol. Sci. 2021, 22(11), 6070; https://doi.org/10.3390/ijms22116070 - 4 Jun 2021
Cited by 6 | Viewed by 3646
Abstract
The approval of the first HIV-1 protease inhibitors (HIV-1 PRIs) marked a fundamental step in the control of AIDS, and this class of agents still represents the mainstay therapy for this illness. Despite the undisputed benefits, the necessary lifelong treatment led to numerous [...] Read more.
The approval of the first HIV-1 protease inhibitors (HIV-1 PRIs) marked a fundamental step in the control of AIDS, and this class of agents still represents the mainstay therapy for this illness. Despite the undisputed benefits, the necessary lifelong treatment led to numerous severe side-effects (metabolic syndrome, hepatotoxicity, diabetes, etc.). The HIV-1 PRIs are capable of interacting with “secondary” targets (off-targets) characterized by different biological activities from that of HIV-1 protease. In this scenario, the in-silico techniques undoubtedly contributed to the design of new small molecules with well-fitting selectivity against the main target, analyzing possible undesirable interactions that are already in the early stages of the research process. The present work is focused on a new mixed-hierarchical, ligand-structure-based protocol, which is centered on an on/off-target approach, to identify the new selective inhibitors of HIV-1 PR. The use of the well-established, ligand-based tools available in the DRUDIT web platform, in combination with a conventional, structure-based molecular docking process, permitted to fast screen a large database of active molecules and to select a set of structure with optimal on/off-target profiles. Therefore, the method exposed herein, could represent a reliable help in the research of new selective targeted small molecules, permitting to design new agents without undesirable interactions. Full article
(This article belongs to the Special Issue Application of In Silico Techniques in Drug Design)
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21 pages, 5523 KiB  
Article
In Silico Identification of Small Molecules as New Cdc25 Inhibitors through the Correlation between Chemosensitivity and Protein Expression Pattern
by Antonino Lauria, Annamaria Martorana, Gabriele La Monica, Salvatore Mannino, Giuseppe Mannino, Daniele Peri and Carla Gentile
Int. J. Mol. Sci. 2021, 22(7), 3714; https://doi.org/10.3390/ijms22073714 - 2 Apr 2021
Cited by 13 | Viewed by 4677
Abstract
The cell division cycle 25 (Cdc25) protein family plays a crucial role in controlling cell proliferation, making it an excellent target for cancer therapy. In this work, a set of small molecules were identified as Cdc25 modulators by applying a mixed ligand-structure-based approach [...] Read more.
The cell division cycle 25 (Cdc25) protein family plays a crucial role in controlling cell proliferation, making it an excellent target for cancer therapy. In this work, a set of small molecules were identified as Cdc25 modulators by applying a mixed ligand-structure-based approach and taking advantage of the correlation between the chemosensitivity of selected structures and the protein expression pattern of the proposed target. In the first step of the in silico protocol, a set of molecules acting as Cdc25 inhibitors were identified through a new ligand-based protocol and the evaluation of a large database of molecular structures. Subsequently, induced-fit docking (IFD) studies allowed us to further reduce the number of compounds biologically screened. In vitro antiproliferative and enzymatic inhibition assays on the selected compounds led to the identification of new structurally heterogeneous inhibitors of Cdc25 proteins. Among them, J3955, the most active inhibitor, showed concentration-dependent antiproliferative activity against HepG2 cells, with GI50 in the low micromolar range. When J3955 was tested in cell-cycle perturbation experiments, it caused mitotic failure by G2/M-phase cell-cycle arrest. Finally, Western blotting analysis showed an increment of phosphorylated Cdk1 levels in cells exposed to J3955, indicating its specific influence in cellular pathways involving Cdc25 proteins. Full article
(This article belongs to the Special Issue Application of In Silico Techniques in Drug Design)
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Review

Jump to: Research

22 pages, 6679 KiB  
Review
Commercial SARS-CoV-2 Targeted, Protease Inhibitor Focused and Protein–Protein Interaction Inhibitor Focused Molecular Libraries for Virtual Screening and Drug Design
by Sebastjan Kralj, Marko Jukič and Urban Bren
Int. J. Mol. Sci. 2022, 23(1), 393; https://doi.org/10.3390/ijms23010393 - 30 Dec 2021
Cited by 10 | Viewed by 3140
Abstract
Since December 2019, the new SARS-CoV-2-related COVID-19 disease has caused a global pandemic and shut down the public life worldwide. Several proteins have emerged as potential therapeutic targets for drug development, and we sought out to review the commercially available and marketed SARS-CoV-2-targeted [...] Read more.
Since December 2019, the new SARS-CoV-2-related COVID-19 disease has caused a global pandemic and shut down the public life worldwide. Several proteins have emerged as potential therapeutic targets for drug development, and we sought out to review the commercially available and marketed SARS-CoV-2-targeted libraries ready for high-throughput virtual screening (HTVS). We evaluated the SARS-CoV-2-targeted, protease-inhibitor-focused and protein–protein-interaction-inhibitor-focused libraries to gain a better understanding of how these libraries were designed. The most common were ligand- and structure-based approaches, along with various filtering steps, using molecular descriptors. Often, these methods were combined to obtain the final library. We recognized the abundance of targeted libraries offered and complimented by the inclusion of analytical data; however, serious concerns had to be raised. Namely, vendors lack the information on the library design and the references to the primary literature. Few references to active compounds were also provided when using the ligand-based design and usually only protein classes or a general panel of targets were listed, along with a general reference to the methods, such as molecular docking for the structure-based design. No receptor data, docking protocols or even references to the applied molecular docking software (or other HTVS software), and no pharmacophore or filter design details were given. No detailed functional group or chemical space analyses were reported, and no specific orientation of the libraries toward the design of covalent or noncovalent inhibitors could be observed. All libraries contained pan-assay interference compounds (PAINS), rapid elimination of swill compounds (REOS) and aggregators, as well as focused on the drug-like model, with the majority of compounds possessing their molecular mass around 500 g/mol. These facts do not bode well for the use of the reviewed libraries in drug design and lend themselves to commercial drug companies to focus on and improve. Full article
(This article belongs to the Special Issue Application of In Silico Techniques in Drug Design)
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