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In Silico Activity Profiling of Natural Products

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A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Natural Products Chemistry".

Deadline for manuscript submissions: closed (15 May 2022) | Viewed by 32557

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Dr. Ilza Pajeva

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Department of QSAR and Molecular Modelling, Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, 1113 Sofia, Bulgaria
Interests: computer-aided drug design; computational toxicology; natural compounds; multidrug resistance; ABC transporters; nuclear receptors; drug-membrane interactions

Dr. Mattia Mori

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Guest Editor

Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Via Aldo Moro 2, 53100 Siena, Italy
Interests: zinc-binding proteins; medicinal chemistry; molecular dynamics; virtual screening; natural products; antiviral agents; anticancer agents; chemoinformatics; computational structural biology; lead optimization
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Special Issue Information

Dear Colleagues,

Natural products are well recognized sources of bioactive compounds and they have been studied to find lead structures for years. In recent years, the interest towards compounds of natural origin has increased tremendously due to their growing use as pharmaceuticals and herbal drugs, components of dietary supplements, and cosmetics. Advances in biotechnology have added new impetus to this trend, thus requiring a more extensive evaluation of the pharmacological properties of bioactive compounds of natural origin.

In parallel, computer-aided or in silico methods constitute an integral part of any modern drug research project addressing all aspects of drug action. The role of the in silico models is indisputable for both, directing the rational design of new bioactive molecules and explaining experimental results, thus interacting with and complementing effectively the “wet” experiments on an equal basis. Simultaneously, in silico methods are also developing rapidly, making use of new and more sophisticated artificial intelligence techniques and simulation methods, and more powerful computational facilities.

In this Special Issue of Molecules, we invite the scientific community to submit original research contributions, short communications or review articles that report on the most recent achievements in the development and application of in silico approaches with a special focus on the investigation of natural products. Our aim is to allow the colleagues that work in this field to present their most advanced and reliable findings as well as prospective results. The studies can address pharmacokinetic and pharmacodynamic aspects of the bioactive compound making use of a broad arsenal of in silico approaches such as ligand- and structure-based methods, molecular dynamics simulations, as well as their combination. The incorporation of experimental means of verification of theoretical studies in submitted manuscripts will be considered as a plus.

Dr. Ilza Pajeva
Dr. Mattia Mori
Guest Editors

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Keywords

Natural products
In silico methods
Pharmacological activity
Computational
Artificial intelligence
Bioactivity prediction

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Published Papers (9 papers)

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Research

15 pages, 2907 KiB

Open AccessArticle

In Vitro and In Silico Investigation of Diterpenoid Alkaloids Isolated from Delphinium chitralense

by Shujaat Ahmad, Manzoor Ahmad, Mazen Almehmadi, Syed Adnan Ali Shah, Farman Ali Khan, Nasir Mehmood Khan, Asifullah Khan, Zainab, Mustafa Halawi and Hanif Ahmad

Molecules 2022, 27(14), 4348; https://doi.org/10.3390/molecules27144348 - 7 Jul 2022

Cited by 5 | Viewed by 2431

Abstract

This study reports the isolation of three new C₂₀ diterpenoid alkaloids, Chitralinine A–C (1–3) from the aerial parts of Delphinium chitralense. Their structures were established on the basis of latest spectral techniques and single crystal X-rays crystallographic studies of chitralinine A described basic skeleton of these compounds. All the isolated Compounds (1–3) showed strong, competitive type inhibition against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in comparison to standard allanzanthane and galanthamine however, chitralinine-C remained the most potent with IC₅₀ value of 11.64 ± 0.08 μM against AChE, and 24.31 ± 0.33 μM against BChE, respectively. The molecular docking reflected a binding free energy of −16.400 K Cal-mol⁻¹ for chitralinine-C, having strong interactions with active site residues, TYR334, ASP72, SER122, and SER200. The overall findings suggest that these new diterpenoid alkaloids could serve as lead drugs against dementia-related diseases including Alzheimer’s disease. Full article

(This article belongs to the Special Issue In Silico Activity Profiling of Natural Products)

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33 pages, 25129 KiB

Open AccessArticle

Computational Study of Asian Propolis Compounds as Potential Anti-Type 2 Diabetes Mellitus Agents by Using Inverse Virtual Screening with the DIA-DB Web Server, Tanimoto Similarity Analysis, and Molecular Dynamic Simulation

by Putri Hawa Syaifie, Azza Hanif Harisna, Mochammad Arfin Fardiansyah Nasution, Adzani Gaisani Arda, Dwi Wahyu Nugroho, Muhammad Miftah Jauhar, Etik Mardliyati, Nurwenda Novan Maulana, Nurul Taufiqu Rochman, Alfian Noviyanto, Antonio J. Banegas-Luna and Horacio Pérez-Sánchez

Molecules 2022, 27(13), 3972; https://doi.org/10.3390/molecules27133972 - 21 Jun 2022

Cited by 12 | Viewed by 3776

Abstract

Propolis contains a wide range of pharmacological activities because of their various bioactive compounds. The beneficial effect of propolis is interesting for treating type-2 diabetes mellitus (T2DM) owing to dysregulation of multiple metabolic processes. In this study, 275 of 658 Asian propolis compounds were evaluated as potential anti-T2DM agents using the DIA-DB web server towards 18 known anti-diabetes protein targets. More than 20% of all compounds could bind to more than five diabetes targets with high binding affinity (<−9.0 kcal/mol). Filtering with physicochemical and pharmacokinetic properties, including ADMET parameters, 12 compounds were identified as potential anti-T2DM with favorable ADMET properties. Six of those compounds, (2R)-7,4′-dihydroxy-5-methoxy-8-methylflavone; (RR)-(+)-3′-senecioylkhellactone; 2′,4′,6′-trihydroxy chalcone; alpinetin; pinobanksin-3-O-butyrate; and pinocembrin-5-methyl ether were first reported as anti-T2DM agents. We identified the significant T2DM targets of Asian propolis, namely retinol-binding protein-4 (RBP4) and aldose reductase (AKR1B1) that have important roles in insulin sensitivity and diabetes complication, respectively. Molecular dynamic simulations showed stable interaction of selected propolis compounds in the active site of RBP4 and AKR1B1. These findings suggest that Asian propolis compound may be effective for treatment of T2DM by targeting RBP4 and AKR1B1. Full article

(This article belongs to the Special Issue In Silico Activity Profiling of Natural Products)

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13 pages, 2759 KiB

Open AccessArticle

Voacanga globosa Spirobisindole Alkaloids Exert Antiviral Activity in HIV Latently Infected Cell Lines by Targeting the NF-κB Cascade: In Vitro and In Silico Investigations

by Ma. Sheila M. de Jesus, Allan Patrick G. Macabeo, John Donnie A. Ramos, Von Novi O. de Leon, Kaori Asamitsu and Takashi Okamoto

Molecules 2022, 27(3), 1078; https://doi.org/10.3390/molecules27031078 - 5 Feb 2022

Cited by 5 | Viewed by 3794 | Correction

Abstract

Since the efficiency in the transcription of the HIV genome contributes to the success of viral replication and infectivity, we investigated the downregulating effects of the spirobisindole alkaloids globospiramine (1), deoxyvobtusine (2), and vobtusine lactone (3) from the endemic Philippine medicinal plant, Voacanga globosa, during HIV gene transcription. Alkaloids 1–3 were explored for their inhibitory activity on TNF-α-induced viral replication in two latently HIV-infected cell lines, OM10.1 and J-Lat. The induction of HIV replication from OM10.1 and J-Lat cells elicited by TNF-α was blocked by globospiramine (1) within noncytotoxic concentrations. Furthermore, globospiramine (1) was found to target the NF-ĸB activation cascade in a dose-dependent manner when the transcriptional step at which inhibitory activity is exerted was examined in TNF-α-induced 293 human cells using transient reporter (luciferase) gene expression systems (HIV LTR-luc, ĸB-luc, and mutant ĸB-luc). Interrogation through molecular docking against the NF-ĸB p50/p65 heterodimer and target sites of the subunits comprising the IKK complex revealed high binding affinities of globospiramine (1) against the S281 pocket of the p65 subunit (BE = −9.2 kcal/mol) and the IKKα activation loop (BE = −9.1 kcal/mol). These findings suggest globospiramine (1) as a molecular inspiration to discover new alkaloid-based anti-HIV derivatives. Full article

(This article belongs to the Special Issue In Silico Activity Profiling of Natural Products)

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16 pages, 5027 KiB

Open AccessArticle

Leucosceptoside A from Devil’s Claw Modulates Psoriasis-like Inflammation via Suppression of the PI3K/AKT Signaling Pathway in Keratinocytes

by Ivanka K. Koycheva, Liliya V. Mihaylova, Monika N. Todorova, Zhivka P. Balcheva-Sivenova, Kalina Alipieva, Claudio Ferrante, Giustino Orlando and Milen I. Georgiev

Molecules 2021, 26(22), 7014; https://doi.org/10.3390/molecules26227014 - 20 Nov 2021

Cited by 10 | Viewed by 4355

Abstract

Psoriasis is a chronic inflammatory skin condition characterized by abnormal keratinocyte proliferation and differentiation that is accompanied with dysregulated immune response and abnormal vascularization. Devil’s claw (Harpagophytum procumbens (Burch.) DC. ex Meisn.) tubers extract has been used both systemically and topically for treatment of chronic inflammatory diseases such as arthritis, osteoporosis, inflammatory bowel disease, among others. However, its potential mechanisms of action against psoriasis remains poorly investigated. The human keratinocyte HaCaT cell line is a well-accepted in vitro model system for inflammatory skin disorders such as psoriasis. The present study involved an exploration of the effect of biotechnologically produced H. procumbens (HP) cell suspension extract and pure phenylethanoid glycosides verbascoside (VER) and leucosceptoside A (LEU) in interferon (IFN)-γ/interleukin (IL)-17A/IL-22-stimulated HaCaT cells as a model of psoriasis-like inflammation. Changes in key inflammatory signaling pathways related to psoriasis development were detected by reverse transcription polymerase chain reaction and western blotting. Treatment with LEU, but not VER and HP extract improved psoriasis-related inflammation via suppression of the PI3K/AKT signaling in IFN-γ/IL-17A/IL-22-stimulated HaCaT cells. Our results suggest that LEU may exhibit therapeutic potential against psoriasis by regulating keratinocyte differentiation through inhibition of the PI3K/AKT pathway. Full article

(This article belongs to the Special Issue In Silico Activity Profiling of Natural Products)

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22 pages, 8109 KiB

Open AccessArticle

Computational Analysis of Chemical Space of Natural Compounds Interacting with Sulfotransferases

by Iglika Lessigiarska, Yunhui Peng, Ivanka Tsakovska, Petko Alov, Nathalie Lagarde, Dessislava Jereva, Bruno O. Villoutreix, Arnaud B. Nicot, Ilza Pajeva, Tania Pencheva and Maria A. Miteva

Molecules 2021, 26(21), 6360; https://doi.org/10.3390/molecules26216360 - 21 Oct 2021

Cited by 2 | Viewed by 2267

Abstract

The aim of this study was to investigate the chemical space and interactions of natural compounds with sulfotransferases (SULTs) using ligand- and structure-based in silico methods. An in-house library of natural ligands (hormones, neurotransmitters, plant-derived compounds and their metabolites) reported to interact with SULTs was created. Their chemical structures and properties were compared to those of compounds of non-natural (synthetic) origin, known to interact with SULTs. The natural ligands interacting with SULTs were further compared to other natural products for which interactions with SULTs were not known. Various descriptors of the molecular structures were calculated and analyzed. Statistical methods (ANOVA, PCA, and clustering) were used to explore the chemical space of the studied compounds. Similarity search between the compounds in the different groups was performed with the ROCS software. The interactions with SULTs were additionally analyzed by docking into different experimental and modeled conformations of SULT1A1. Natural products with potentially strong interactions with SULTs were outlined. Our results contribute to a better understanding of chemical space and interactions of natural compounds with SULT enzymes and help to outline new potential ligands of these enzymes. Full article

(This article belongs to the Special Issue In Silico Activity Profiling of Natural Products)

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13 pages, 3231 KiB

Open AccessArticle

A Comprehensive Computational Screening of Phytochemicals Derived from Saudi Medicinal Plants against Human CC Chemokine Receptor 7 to Identify Potential Anti-Cancer Therapeutics

by Faris Alrumaihi

Molecules 2021, 26(21), 6354; https://doi.org/10.3390/molecules26216354 - 21 Oct 2021

Cited by 3 | Viewed by 2304

Abstract

Homeostatic trafficking of immune cells by CC chemokine receptor 7 (CCR7) keeps immune responses and tolerance in a balance. The involvement of this protein in lymph node metastasis in cancer marks CCR7 as a penitential drug target. Using the crystal structure of CCR7, herein, a comprehensive virtual screening study is presented to filter novel strong CCR7 binding phytochemicals from Saudi medicinal plants that have a higher binding affinity for the intracellular allosteric binding pocket. By doing so, three small natural molecules named as Hit-1 (1,8,10-trihydroxy-3-methoxy-6-methylanthracen-9(4H)-one), Hit-2 (4-(3,4-dimethoxybenzyl)-3-(4-hydroxy-3-methoxybenzyl)dihydrofuran-2(3H)-one), and Hit-3 (10-methyl-12,13-dihydro-[1,2]dioxolo[3,4,5-de]furo[3,2-g]isochromeno[4,3-b]chromen-8-ol) are predicted showing strong binding potential for the CC chemokine receptor 7 allosteric pocket. During molecular dynamics simulations, the compounds were observed in the formation of several chemical bonding of short bond distances. Additionally, the molecules remained in strong contact with the active pocket residues and experienced small conformation changes that seemed to be mediated by the CCR7 loops to properly engage the ligands. Two types of binding energy methods (MM/GBPBSA and WaterSwap) were additionally applied to further validate docking and simulation findings. Both analyses complement the good affinity of compounds for CCR7, the electrostatic and van der Waals energies being the most dominant in intermolecular interactions. The active pocket residue’s role in compounds binding was further evaluated via alanine scanning, which highlighted their importance in natural compounds binding. Additionally, the compounds fulfilled all drug-like rules: Lipinski, Ghose, Veber, Egan, and Muegge passed many safety parameters, making them excellent anti-cancer candidates for experimental testing. Full article

(This article belongs to the Special Issue In Silico Activity Profiling of Natural Products)

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23 pages, 3888 KiB

Open AccessArticle

In Silico Evaluation of Iranian Medicinal Plant Phytoconstituents as Inhibitors against Main Protease and the Receptor-Binding Domain of SARS-CoV-2

by Seyyed Sasan Mousavi, Akbar Karami, Tahereh Movahhed Haghighi, Sefren Geiner Tumilaar, Fatimawali, Rinaldi Idroes, Shafi Mahmud, Ismail Celik, Duygu Ağagündüz, Trina Ekawati Tallei, Talha Bin Emran and Raffaele Capasso

Molecules 2021, 26(18), 5724; https://doi.org/10.3390/molecules26185724 - 21 Sep 2021

Cited by 48 | Viewed by 5304

Abstract

The novel coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which initially appeared in Wuhan, China, in December 2019. Elderly individuals and those with comorbid conditions may be more vulnerable to this disease. Consequently, several research laboratories continue to focus on developing drugs to treat this infection because this disease has developed into a global pandemic with an extremely limited number of specific treatments available. Natural herbal remedies have long been used to treat illnesses in a variety of cultures. Modern medicine has achieved success due to the effectiveness of traditional medicines, which are derived from medicinal plants. The objective of this study was to determine whether components of natural origin from Iranian medicinal plants have an antiviral effect that can prevent humans from this coronavirus infection using the most reliable molecular docking method; in our case, we focused on the main protease (M^pro) and a receptor-binding domain (RBD). The results of molecular docking showed that among 169 molecules of natural origin from common Iranian medicinal plants, 20 molecules (chelidimerine, rutin, fumariline, catechin gallate, adlumidine, astragalin, somniferine, etc.) can be proposed as inhibitors against this coronavirus based on the binding free energy and type of interactions between these molecules and the studied proteins. Moreover, a molecular dynamics simulation study revealed that the chelidimerine–M^pro and somniferine–RBD complexes were stable for up to 50 ns below 0.5 nm. Our results provide valuable insights into this mechanism, which sheds light on future structure-based designs of high-potency inhibitors for SARS-CoV-2. Full article

(This article belongs to the Special Issue In Silico Activity Profiling of Natural Products)

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22 pages, 6486 KiB

Open AccessArticle

Cheminformatic Profiling and Hit Prioritization of Natural Products with Activities against Methicillin-Resistant Staphylococcus aureus (MRSA)

by Samson O. Oselusi, Samuel A. Egieyeh and Alan Christoffels

Molecules 2021, 26(12), 3674; https://doi.org/10.3390/molecules26123674 - 16 Jun 2021

Cited by 11 | Viewed by 2994

Abstract

Several natural products (NPs) have displayed varying in vitro activities against methicillin-resistant Staphylococcus aureus (MRSA). However, few of these compounds have not been developed into potential antimicrobial drug candidates. This may be due to the high cost and tedious and time-consuming process of conducting the necessary preclinical tests on these compounds. In this study, cheminformatic profiling was performed on 111 anti-MRSA NPs (AMNPs), using a few orally administered conventional drugs for MRSA (CDs) as reference, to identify compounds with prospects to become drug candidates. This was followed by prioritizing these hits and identifying the liabilities among the AMNPs for possible optimization. Cheminformatic profiling revealed that most of the AMNPs were within the required drug-like region of the investigated properties. For example, more than 76% of the AMNPs showed compliance with the Lipinski, Veber, and Egan predictive rules for oral absorption and permeability. About 34% of the AMNPs showed the prospect to penetrate the blood–brain barrier (BBB), an advantage over the CDs, which are generally non-permeant of BBB. The analysis of toxicity revealed that 59% of the AMNPs might have negligible or no toxicity risks. Structure–activity relationship (SAR) analysis revealed chemical groups that may be determinants of the reported bioactivity of the compounds. A hit prioritization strategy using a novel “desirability scoring function” was able to identify AMNPs with the desired drug-likeness. Hit optimization strategies implemented on AMNPs with poor desirability scores led to the design of two compounds with improved desirability scores. Full article

(This article belongs to the Special Issue In Silico Activity Profiling of Natural Products)

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13 pages, 22993 KiB

Open AccessArticle

Effects of Curcumin and Ferulic Acid on the Folding of Amyloid-β Peptide

by Evdokiya Salamanova, Mariyana Atanasova, Ivan Dimitrov and Irini Doytchinova

Molecules 2021, 26(9), 2815; https://doi.org/10.3390/molecules26092815 - 10 May 2021

Cited by 13 | Viewed by 2607

Abstract

The polyphenols curcumin (CU) and ferulic acid (FA) are able to inhibit the aggregation of amyloid-β (Aβ) peptide with different strengths. CU is a strong inhibitor while FA is a weaker one. In the present study, we examine the effects of CU and FA on the folding process of an Aβ monomer by 1 µs molecular dynamics (MD) simulations. We found that both inhibitors increase the helical propensity and decrease the non-helical propensity of Aβ peptide. They prevent the formation of a dense bulk core and shorten the average lifetime of intramolecular hydrogen bonds in Aβ. CU makes more and longer-lived hydrogen bonds, hydrophobic, π–π, and cation–π interactions with Aβ peptide than FA does, which is in a good agreement with the observed stronger inhibitory activity of CU on Aβ aggregation. Full article

(This article belongs to the Special Issue In Silico Activity Profiling of Natural Products)

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