Repurposing approved drugs as inhibitors of SARS-CoV-2 S-protein from molecular modeling and virtual screening

Malarial parasites have been reported for moderate-high resistance towards classical antimalarial agents and henceforth development of newer novel chemical entities targeting multiple targets rather than targeting single target will be a highly promising strategy in antimalarial drug discovery. Herein, we carried out molecular modeling studies on 2,4-disubstituted imidazopyridines as anti-hemozoin formation inhibitors by using Schrödinger’s molecular modeling package (2020_4). We have developed statistically robust atom-based 3D-QSAR model (training set, [Formula: see text]; test set, [Formula: see text]; [Formula: see text] [Formula: see text]; root-mean-square error, [Formula: see text]; standard deviation, [Formula: see text]). Our molecular docking, in-silico ADMET analysis showed that dataset molecule 37, has highly promising results. Our ligand-based virtual screening resulted in top five ZINC hits, among them ZINC73737443 hit was observed with lesser energy gap, i.e. 7.85[Formula: see text]eV, higher softness value (0.127[Formula: see text]eV), and comparatively good docking score of [Formula: see text]10.2[Formula: see text]kcal/mol. Our in-silico analysis for a proposed hit, ZINC73737443 showed that this molecule has good ADMET, in-silico nonames toxic as well as noncarcinogenic profile. We believe that further experimental as well as the in-vitro investigation will throw more lights on the identification of ZINC73737443 as a potential antimalarial agent.

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Palbociclib and Ribociclib Analogs Targeting CDK4 and CDK6 for Breast Cancer Treatment: A Molecular Modeling Study

10.26434/chemrxiv.12902504.v1 ◽

2020 ◽

Author(s):

Dhoha TRIKI ◽

sravya Kuchibhotla ◽

Denis Fourches

Keyword(s):

Breast Cancer ◽

Molecular Modeling ◽

Breast Cancer Treatment ◽

Large Set ◽

Dynamic Interactions ◽

Cyclin Dependent Kinases ◽

Highly Active ◽

Approved Drugs ◽

Fda Approved Drugs ◽

Treat Breast Cancer

<div>Palbociclib and Ribociclib are FDA approved drugs that target cyclin dependent kinases CDK4 and CDK6 to treat breast cancer. Herein, we conducted a cheminformatics analysis of a large set of their analogs. The study highlights (i) several clusters of similar compounds with excellent inhibitory profiles, (ii) their shared CDK-ligand intermolecular interactions as predicted by 3D docking, and (iii) key dynamic interactions shared by highly active CDK4/6 inhibitors.<br></div>

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Mulberrofuran G, a Potent Inhibitor of SPIKE Protein of SARS Corona Virus 2

Journal of Pharmaceutical Care ◽

10.18502/jpc.v9i2.6610 ◽

2021 ◽

Author(s):

Fatemeh Sadat Hosseini ◽

Mohammad Reza Motamedi

Keyword(s):

Molecular Docking ◽

Virtual Screening ◽

Active Site ◽

Potential Role ◽

Potent Inhibitor ◽

Screening Method ◽

Spike Protein ◽

Treatment Agent ◽

Approved Drugs ◽

Fda Approved Drugs

Background: At the onset of the 2020 year, Coronavirus disease (COVID-19) has become a pandemic and infected many people worldwide. Despite all efforts, no cure was found for this infection. Bioinformatics and medicinal chemistry have a potential role in the primary consideration of drugs to treat this infection. With virtual screening and molecular docking, some potent compounds and medications can be found and modified and then applied to treat disease in the next steps. Methods: By virtual screening method and PRYX software, some Food and Drug Administration (FDA) approved drugs and natural compounds have been docked with the SPIKE protein of SARS-CoV-2. Some more potent agents have been selected, and then new structures are designed with better affinity than them. After that, we searched for the molecules with a similar structure to designed compounds to find the most potent compound to our target. Results: Because of the study of structures and affinities, mulberrofuran G was the most potent compound in this study. The compound has interacted strongly with residues in the probably active site of SPIKE. Conclusion: Mulberrofuran G can be a treatment agent candidate for COVID-19 because of its good affinity to SPIKE of the virus and inhibition of virus-cell adhesion and entrance.

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Virtual screening as therapeutic strategy of COVID-19 targeting angiotensin-converting enzyme 2

Frontiers in Molecular Immunology ◽

10.25082/fmi.2021.01.002 ◽

2021 ◽

Vol 2 (1) ◽

pp. 16-27

Author(s):

Zahra Sharifinia ◽

◽

Samira Asadi ◽

Mahyar Irani ◽

Abdollah Allahverdi ◽

...

Keyword(s):

Virtual Screening ◽

Angiotensin Converting Enzyme ◽

Host Cells ◽

Spike Protein ◽

Potential Drug ◽

Converting Enzyme ◽

Angiotensin Converting Enzyme 2 ◽

Approved Drugs ◽

Fda Approved Drugs

Objective: The receptor-binding domain (RBD) of the S1 domain of the SARS-CoV- 2 Spike protein performs a key role in the interaction with Angiotensin-converting enzyme 2 (ACE2), leading to both subsequent S2 domain-mediated membrane fusion and incorporation of viral RNA in host cells. Methods: In this study, we investigated the inhibitor’s targeted compounds through existing human ACE2 drugs to use as a future viral invasion. 54 FDA approved drugs were selected to assess their binding affinity to the ACE2 receptor. The structurebased methods via computational ones have been used for virtual screening of the best drugs from the drug database. Key Findings: The ligands “Cinacalcet” and “Levomefolic acid” highaffinity scores can be a potential drug preventing Spike protein of SARS-CoV-2 and human ACE2 interaction. Levomefolic acid from vitamin B family was proved to be a potential drug as a spike protein inhibitor in previous clinical and computational studies. Besides that, in this study, the capability of Levomefolic acid to avoid ACE2 and Spike protein of SARS-CoV-2 interaction is indicated. Therefore, it is worth to consider this drug for more in vitro investigations as ACE2 and Spike protein inhibition candidate. Conclusion: The two Cinacalcet and Levomefolic acid are the two ligands that have highest energy binding for human ACE2 blocking among 54 FDA approved drugs.

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