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28 pages, 9844 KiB

Open AccessArticle

Exploring EZH2-Proteasome Dual-Targeting Drug Discovery through a Computational Strategy to Fight Multiple Myeloma

by Filipe G. A. Estrada, Silvia Miccoli, Natália Aniceto, Alfonso T. García-Sosa and Rita C. Guedes

Molecules 2021, 26(18), 5574; https://doi.org/10.3390/molecules26185574 - 14 Sep 2021

Cited by 2 | Viewed by 3816

Abstract

Multiple myeloma is an incurable plasma cell neoplastic disease representing about 10–15% of all haematological malignancies diagnosed in developed countries. Proteasome is a key player in multiple myeloma and proteasome inhibitors are the current first-line of treatment. However, these are associated with limited [...] Read more.

Multiple myeloma is an incurable plasma cell neoplastic disease representing about 10–15% of all haematological malignancies diagnosed in developed countries. Proteasome is a key player in multiple myeloma and proteasome inhibitors are the current first-line of treatment. However, these are associated with limited clinical efficacy due to acquired resistance. One of the solutions to overcome this problem is a polypharmacology approach, namely combination therapy and multitargeting drugs. Several polypharmacology avenues are currently being explored. The simultaneous inhibition of EZH2 and Proteasome 20S remains to be investigated, despite the encouraging evidence of therapeutic synergy between the two. Therefore, we sought to bridge this gap by proposing a holistic in silico strategy to find new dual-target inhibitors. First, we assessed the characteristics of both pockets and compared the chemical space of EZH2 and Proteasome 20S inhibitors, to establish the feasibility of dual targeting. This was followed by molecular docking calculations performed on EZH2 and Proteasome 20S inhibitors from ChEMBL 25, from which we derived a predictive model to propose new EZH2 inhibitors among Proteasome 20S compounds, and vice versa, which yielded two dual-inhibitor hits. Complementarily, we built a machine learning QSAR model for each target but realised their application to our data is very limited as each dataset occupies a different region of chemical space. We finally proceeded with molecular dynamics simulations of the two docking hits against the two targets. Overall, we concluded that one of the hit compounds is particularly promising as a dual-inhibitor candidate exhibiting extensive hydrogen bonding with both targets. Furthermore, this work serves as a framework for how to rationally approach a dual-targeting drug discovery project, from the selection of the targets to the prediction of new hit compounds. Full article

(This article belongs to the Special Issue Designed Multiple Ligands in Drug Design and Development)

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16 pages, 32665 KiB

Open AccessArticle

Conformational Selection Mechanism Provides Structural Insights into the Optimization of APC-Asef Inhibitors

by Xinheng He, Ning Huang, Yuran Qiu, Jian Zhang, Yaqin Liu, Xiao-Lan Yin and Shaoyong Lu

Molecules 2021, 26(4), 962; https://doi.org/10.3390/molecules26040962 - 11 Feb 2021

Cited by 11 | Viewed by 2425

Abstract

Metastasis is the major cause of death in colorectal cancer and it has been proven that inhibiting an interaction between adenomatous polyposis coli (APC) and Rho guanine nucleotide exchange factor 4 (Asef) efficaciously restrain metastasis. However, current inhibitors cannot achieve a satisfying effect [...] Read more.

Metastasis is the major cause of death in colorectal cancer and it has been proven that inhibiting an interaction between adenomatous polyposis coli (APC) and Rho guanine nucleotide exchange factor 4 (Asef) efficaciously restrain metastasis. However, current inhibitors cannot achieve a satisfying effect in vivo and need to be optimized. In the present study, we applied molecular dynamics (MD) simulations and extensive analyses to apo and holo APC systems in order to reveal the inhibitor mechanism in detail and provide insights into optimization. MD simulations suggested that apo APC takes on a broad array of conformations and inhibitors stabilize conformation selectively. Representative structures in trajectories show specific APC-ligand interactions, explaining the different binding process. The stability and dynamic properties of systems elucidate the inherent factors of the conformation selection mechanism. Binding free energy analysis quantitatively confirms key interface residues and guide optimization. This study elucidates the conformation selection mechanism in APC-Asef inhibition and provides insights into peptide-based drug design. Full article

(This article belongs to the Special Issue Designed Multiple Ligands in Drug Design and Development)

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19 pages, 965 KiB

Open AccessArticle

Design, Synthesis, and In Silico Multitarget Pharmacological Simulations of Acid Bioisosteres with a Validated In Vivo Antihyperglycemic Effect

by Elix Alberto Domínguez-Mendoza, Yelzyn Galván-Ciprés, Josué Martínez-Miranda, Cristian Miranda-González, Blanca Colín-Lozano, Emanuel Hernández-Núñez, Gloria I. Hernández-Bolio, Oscar Palomino-Hernández and Gabriel Navarrete-Vazquez

Molecules 2021, 26(4), 799; https://doi.org/10.3390/molecules26040799 - 4 Feb 2021

Cited by 11 | Viewed by 4107

Abstract

Substituted phenylacetic (1–3), phenylpropanoic (4–6), and benzylidenethiazolidine-2,4-dione (7–9) derivatives were designed according to a multitarget unified pharmacophore pattern that has shown robust antidiabetic activity. This bioactivity is due to the simultaneous polypharmacological stimulation of receptors PPARα, PPARγ, [...] Read more.

Substituted phenylacetic (1–3), phenylpropanoic (4–6), and benzylidenethiazolidine-2,4-dione (7–9) derivatives were designed according to a multitarget unified pharmacophore pattern that has shown robust antidiabetic activity. This bioactivity is due to the simultaneous polypharmacological stimulation of receptors PPARα, PPARγ, and GPR40 and the enzyme inhibition of aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP-1B). The nine compounds share the same four pharmacophore elements: an acid moiety, an aromatic ring, a bulky hydrophobic group, and a flexible linker between the latter two elements. Addition and substitution reactions were performed to obtain molecules at moderated yields. In silico pharmacological consensus analysis (PHACA) was conducted to determine their possible modes of action, protein affinities, toxicological activities, and drug-like properties. The results were combined with in vivo assays to evaluate the ability of these compounds to decrease glucose levels in diabetic mice at a 100 mg/kg single dose. Compounds 6 (a phenylpropanoic acid derivative) and 9 (a benzylidenethiazolidine-2,4-dione derivative) ameliorated the hyperglycemic peak in a statically significant manner in a mouse model of type 2 diabetes. Finally, molecular dynamics simulations were executed on the top performing compounds to shed light on their mechanism of action. The simulations showed the flexible nature of the binding pocket of AR, and showed that both compounds remained bound during the simulation time, although not sharing the same binding mode. In conclusion, we designed nine acid bioisosteres with robust in vivo antihyperglycemic activity that were predicted to have favorable pharmacokinetic and toxicological profiles. Together, these findings provide evidence that supports the molecular design we employed, where the unified pharmacophores possess a strong antidiabetic action due to their multitarget activation. Full article

(This article belongs to the Special Issue Designed Multiple Ligands in Drug Design and Development)

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32 pages, 8728 KiB

Open AccessFeature PaperArticle

In Search for Multi-Target Ligands as Potential Agents for Diabetes Mellitus and Its Complications—A Structure-Activity Relationship Study on Inhibitors of Aldose Reductase and Protein Tyrosine Phosphatase 1B

by Rosaria Ottanà, Paolo Paoli, Mario Cappiello, Trung Ngoc Nguyen, Ilenia Adornato, Antonella Del Corso, Massimo Genovese, Ilaria Nesi, Roberta Moschini, Alexandra Naß, Gerhard Wolber and Rosanna Maccari

Molecules 2021, 26(2), 330; https://doi.org/10.3390/molecules26020330 - 10 Jan 2021

Cited by 19 | Viewed by 4400

Abstract

Diabetes mellitus (DM) is a complex disease which currently affects more than 460 million people and is one of the leading cause of death worldwide. Its development implies numerous metabolic dysfunctions and the onset of hyperglycaemia-induced chronic complications. Multiple ligands can be rationally [...] Read more.

Diabetes mellitus (DM) is a complex disease which currently affects more than 460 million people and is one of the leading cause of death worldwide. Its development implies numerous metabolic dysfunctions and the onset of hyperglycaemia-induced chronic complications. Multiple ligands can be rationally designed for the treatment of multifactorial diseases, such as DM, with the precise aim of simultaneously controlling multiple pathogenic mechanisms related to the disease and providing a more effective and safer therapeutic treatment compared to combinations of selective drugs. Starting from our previous findings that highlighted the possibility to target both aldose reductase (AR) and protein tyrosine phosphatase 1B (PTP1B), two enzymes strictly implicated in the development of DM and its complications, we synthesised 3-(5-arylidene-4-oxothiazolidin-3-yl)propanoic acids and analogous 2-butenoic acid derivatives, with the aim of balancing the effectiveness of dual AR/PTP1B inhibitors which we had identified as designed multiple ligands (DMLs). Out of the tested compounds, 4f exhibited well-balanced AR/PTP1B inhibitory effects at low micromolar concentrations, along with interesting insulin-sensitizing activity in murine C2C12 cell cultures. The SARs here highlighted along with their rationalization by in silico docking experiments into both target enzymes provide further insights into this class of inhibitors for their development as potential DML antidiabetic candidates. Full article

(This article belongs to the Special Issue Designed Multiple Ligands in Drug Design and Development)

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Review

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15 pages, 1113 KiB

Open AccessReview

Insights into the Protective Effects of Thymoquinone against Toxicities Induced by Chemotherapeutic Agents

by Juveriya Farooq, Rokeya Sultana, Tahreen Taj, Syed Mohammed Basheeruddin Asdaq, Abdulkhaliq J. Alsalman, Mohammed Al Mohaini, Maitham A. Al Hawaj, Mehnaz Kamal, Saad Alghamdi, Mohd. Imran, Haleema Shahin and Ruheena Tabassum

Molecules 2022, 27(1), 226; https://doi.org/10.3390/molecules27010226 - 30 Dec 2021

Cited by 12 | Viewed by 3378

Abstract

The drugs used to treat cancer not only kill fast-growing cancer cells, but also kill or slow the growth of healthy cells, causing systemic toxicities that lead to altered functioning of normal cells. Most chemotherapeutic agents have serious toxicities associated with their use, [...] Read more.

The drugs used to treat cancer not only kill fast-growing cancer cells, but also kill or slow the growth of healthy cells, causing systemic toxicities that lead to altered functioning of normal cells. Most chemotherapeutic agents have serious toxicities associated with their use, necessitating extreme caution and attention. There is a growing interest in herbal remedies because of their pharmacological activities, minimal side effects, and low cost. Thymoquinone, a major component of the volatile oil of Nigella sativa Linn, also known as black cumin or black seeds, is commonly used in Middle Eastern countries as a condiment. It is also utilized for medicinal purposes and possesses antidiabetic, anti-cancer, anti-inflammatory, hepatoprotective, anti-microbial, immunomodulatory, and antioxidant properties. This review attempts to compile the published literature demonstrating thymoquinone’s protective effect against chemotherapeutic drug-induced toxicities. Full article

(This article belongs to the Special Issue Designed Multiple Ligands in Drug Design and Development)

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18 pages, 2186 KiB

Open AccessReview

Discovery, Development, and Patent Trends on Molnupiravir: A Prospective Oral Treatment for COVID-19

by Mohd. Imran, Mandeep Kumar Arora, Syed Mohammed Basheeruddin Asdaq, Shah Alam Khan, Saleh I. Alaqel, Mohammed Kanan Alshammari, Mohammed M. Alshehri, Ahmed Subeh Alshrari, Alreshidi Mateq Ali, Ahmed Muteb Al-shammeri, Bushra Dhuhayyan Alhazmi, Aishah Ali Harshan, Md. Tauquir Alam and Abida

Molecules 2021, 26(19), 5795; https://doi.org/10.3390/molecules26195795 - 24 Sep 2021

Cited by 131 | Viewed by 21581

Abstract

The COVID-19 pandemic needs no introduction at present. Only a few treatments are available for this disease, including remdesivir and favipiravir. Accordingly, the pharmaceutical industry is striving to develop new treatments for COVID-19. Molnupiravir, an orally active RdRp inhibitor, is in a phase [...] Read more.

The COVID-19 pandemic needs no introduction at present. Only a few treatments are available for this disease, including remdesivir and favipiravir. Accordingly, the pharmaceutical industry is striving to develop new treatments for COVID-19. Molnupiravir, an orally active RdRp inhibitor, is in a phase 3 clinical trial against COVID-19. The objective of this review article is to enlighten the researchers working on COVID-19 about the discovery, recent developments, and patents related to molnupiravir. Molnupiravir was originally developed for the treatment of influenza at Emory University, USA. However, this drug has also demonstrated activity against a variety of viruses, including SARS-CoV-2. Now it is being jointly developed by Emory University, Ridgeback Biotherapeutics, and Merck to treat COVID-19. The published clinical data indicate a good safety profile, tolerability, and oral bioavailability of molnupiravir in humans. The patient-compliant oral dosage form of molnupiravir may hit the market in the first or second quarter of 2022. The patent data of molnupiravir revealed its granted compound patent and process-related patent applications. We also anticipate patent filing related to oral dosage forms, inhalers, and a combination of molnupiravir with marketed drugs like remdesivir, favipiravir, and baricitinib. The current pandemic demands a patient compliant, safe, tolerable, and orally effective COVID-19 treatment. The authors believe that molnupiravir meets these requirements and is a breakthrough COVID-19 treatment. Full article

(This article belongs to the Special Issue Designed Multiple Ligands in Drug Design and Development)

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34 pages, 4189 KiB

Open AccessFeature PaperReview

Natural α-Glucosidase and Protein Tyrosine Phosphatase 1B Inhibitors: A Source of Scaffold Molecules for Synthesis of New Multitarget Antidiabetic Drugs

by Massimo Genovese, Ilaria Nesi, Anna Caselli and Paolo Paoli

Molecules 2021, 26(16), 4818; https://doi.org/10.3390/molecules26164818 - 9 Aug 2021

Cited by 17 | Viewed by 3808

Abstract

Diabetes mellitus (DM) represents a group of metabolic disorders that leads to acute and long-term serious complications and is considered a worldwide sanitary emergence. Type 2 diabetes (T2D) represents about 90% of all cases of diabetes, and even if several drugs are actually [...] Read more.

Diabetes mellitus (DM) represents a group of metabolic disorders that leads to acute and long-term serious complications and is considered a worldwide sanitary emergence. Type 2 diabetes (T2D) represents about 90% of all cases of diabetes, and even if several drugs are actually available for its treatment, in the long term, they show limited effectiveness. Most traditional drugs are designed to act on a specific biological target, but the complexity of the current pathologies has demonstrated that molecules hitting more than one target may be safer and more effective. The purpose of this review is to shed light on the natural compounds known as α-glucosidase and Protein Tyrosine Phosphatase 1B (PTP1B) dual-inhibitors that could be used as lead compounds to generate new multitarget antidiabetic drugs for treatment of T2D. Full article

(This article belongs to the Special Issue Designed Multiple Ligands in Drug Design and Development)

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33 pages, 9087 KiB

Open AccessReview

Development of Novel Indole-Based Bifunctional Aldose Reductase Inhibitors/Antioxidants as Promising Drugs for the Treatment of Diabetic Complications

by Lucia Kovacikova, Marta Soltesova Prnova, Magdalena Majekova, Andrej Bohac, Cimen Karasu and Milan Stefek

Molecules 2021, 26(10), 2867; https://doi.org/10.3390/molecules26102867 - 12 May 2021

Cited by 17 | Viewed by 4664

Abstract

Aldose reductase (AR, ALR2), the first enzyme of the polyol pathway, is implicated in the pathophysiology of diabetic complications. Aldose reductase inhibitors (ARIs) thus present a promising therapeutic approach to treat a wide array of diabetic complications. Moreover, a therapeutic potential of ARIs [...] Read more.

Aldose reductase (AR, ALR2), the first enzyme of the polyol pathway, is implicated in the pathophysiology of diabetic complications. Aldose reductase inhibitors (ARIs) thus present a promising therapeutic approach to treat a wide array of diabetic complications. Moreover, a therapeutic potential of ARIs in the treatment of chronic inflammation-related pathologies and several genetic metabolic disorders has been recently indicated. Substituted indoles are an interesting group of compounds with a plethora of biological activities. This article reviews a series of indole-based bifunctional aldose reductase inhibitors/antioxidants (ARIs/AOs) developed during recent years. Experimental results obtained in in vitro, ex vivo, and in vivo models of diabetic complications are presented. Structure–activity relationships with respect to carboxymethyl pharmacophore regioisomerization and core scaffold modification are discussed along with the criteria of ‘drug-likeness”. Novel promising structures of putative multifunctional ARIs/AOs are designed. Full article

(This article belongs to the Special Issue Designed Multiple Ligands in Drug Design and Development)

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