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Structure-activity relationship (SAR) and molecular dynamics study of withaferin-A fragment derivatives as potential therapeutic lead against main protease (M^pro) of SARS-CoV-2.

ABSTRACT: The spread of novel coronavirus SARS-CoV-2 has directed to a state of an unprecedented global pandemic. Many synthetic compounds and FDA-approved drugs have been significantly inhibitory against the virus, but no SARS-CoV-2 solution has been identified. However, small molecule fragment-based derivatives of potent phytocompounds may serve as promising inhibitors against SARS-CoV-2. In the pursuit of exploring novel SARS-CoV-2 inhibitors, we generated small molecule fragment derivatives from potent phytocompounds using neural networking and machine learning-based tools, which can cover unexplored regions of the chemical space that still retain lead-like properties. Out of 300 derivative molecules from withaferin-A, hesperidin, and baicalin, 30 were screened out with synthetic accessibility scores >?4 having the best ADME properties. The withaferin-A derivative molecules 61 and 64 exhibited a significant binding affinity of -?7.84 kcal/mol and -?7.94 kcal/mol. The docking study reveals that withaferin-A mol 61 forms 5 polar H-bonds with the M^pro where amino acids involved are GLU166, THR190, CYS145, MET165, and GLN152 and upon QSAR analysis showed a minimal predicted IC50 value of 7762.47 nM. Furthermore, the in silico cytotoxicity predictions, pharmacophore modeling, and molecular dynamics simulation studies have resulted in predicting the highly potent small molecule derivative from withaferin-A (phytocompound from Withania somnifera) to be the potential inhibitor of SARS-CoV 2 protease (M^pro) and a promising future lead candidate against COVID-19. The rationale of choosing withaferin-A from Withania somnifera (Ashwagandha) was propelled by the innumerous applications of Ashwagandha for the treatment of various antiviral diseases, common cold, and fever since time immemorial. Graphical abstract.

SUBMITTER: Ghosh A

PROVIDER: S-EPMC7914120 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Structure-activity relationship (SAR) and molecular dynamics study of withaferin-A fragment derivatives as potential therapeutic lead against main protease (M<sup>pro</sup>) of SARS-CoV-2.

Ghosh Arabinda A Chakraborty Monoswi M Chandra Anshuman A Alam Mohamad Parvez MP

Journal of molecular modeling 20210228 3

The spread of novel coronavirus SARS-CoV-2 has directed to a state of an unprecedented global pandemic. Many synthetic compounds and FDA-approved drugs have been significantly inhibitory against the virus, but no SARS-CoV-2 solution has been identified. However, small molecule fragment-based derivatives of potent phytocompounds may serve as promising inhibitors against SARS-CoV-2. In the pursuit of exploring novel SARS-CoV-2 inhibitors, we generated small molecule fragment derivatives from poten ...[more]

PMID: 33641023

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Project description:Over a span of two years ago, since the emergence of the first case of the novel coronavirus (SARS-CoV-2) in China, the pandemic has crossed borders causing serious health emergencies, immense economic crisis and impacting the daily life worldwide. Despite the discovery of numerous forms of precautionary vaccines along with other recently approved orally available drugs, yet effective antiviral therapeutics are necessarily needed to hunt this virus and its variants. Historically, naturally occurring chemicals have always been considered the primary source of beneficial medications. Considering the SARS-CoV-2 main protease (Mpro) as the duplicate key element of the viral cycle and its main target, in this paper, an extensive virtual screening for a focused chemical library of 15 batzelladine marine alkaloids, was virtually examined against SARS-CoV-2 main protease (Mpro) using an integrated set of modern computational tools including molecular docking (MDock), molecule dynamic (MD) simulations and structure-activity relationships (SARs) as well. The molecular docking predictions had disclosed four promising compounds including batzelladines H-I (8-9) and batzelladines F-G (6-7), respectively according to their prominent ligand-protein energy scores and relevant binding affinities with the (Mpro) pocket residues. The best two chemical hits, batzelladines H-I (8-9) were further investigated thermodynamically though studying their MD simulations at 100 ns, where they showed excellent stability within the accommodated (Mpro) pocket. Moreover, SARs studies imply the crucial roles of the fused tricyclic guanidinic moieties, its degree of unsaturation, position of the N-OH functionality and the length of the side chain as a spacer linking between two active sites, which disclosed fundamental structural and pharmacophoric features for efficient protein-ligand interaction. Such interesting findings are greatly highlighting further in vitro/vivo examinations regarding those marine natural products (MNPs) and their synthetic equivalents as promising antivirals.

Dataset Information

Structure-activity relationship (SAR) and molecular dynamics study of withaferin-A fragment derivatives as potential therapeutic lead against main protease (M^pro) of SARS-CoV-2.

Publications

Structure-activity relationship (SAR) and molecular dynamics study of withaferin-A fragment derivatives as potential therapeutic lead against main protease (M<sup>pro</sup>) of SARS-CoV-2.

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Dataset Information

Structure-activity relationship (SAR) and molecular dynamics study of withaferin-A fragment derivatives as potential therapeutic lead against main protease (Mpro) of SARS-CoV-2.

Publications

Structure-activity relationship (SAR) and molecular dynamics study of withaferin-A fragment derivatives as potential therapeutic lead against main protease (M<sup>pro</sup>) of SARS-CoV-2.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Structure-activity relationship (SAR) and molecular dynamics study of withaferin-A fragment derivatives as potential therapeutic lead against main protease (M^pro) of SARS-CoV-2.