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Identification of high affinity and low molecular alternatives of boceprevir against SARS-CoV-2 main protease: A virtual screening approach.

ABSTRACT: SARS-CoV-2 has posed global challenge for healthcare due to COVID-19. The main protease (M^pro) of this virus is considered as a major target for drug development efforts. In this work, we have used virtual screening approach with molecular dynamics simulations to identify high affinity and low molecular weight alternatives of boceprevir, a repurposed drug currently being evaluated against M^pro. Out of 180 compounds screened, two boceprevir analogs (PubChem ID: 57841991 and 58606278) were reported as potential alternatives with comparable predicted protease inhibitor potential and pharmacological properties. Further experimental validation of the reported compounds may contribute to the ongoing investigation of boceprevir.

SUBMITTER: Borkotoky S

PROVIDER: S-EPMC7892318 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Identification of high affinity and low molecular alternatives of boceprevir against SARS-CoV-2 main protease: A virtual screening approach.

Borkotoky Subhomoi S Banerjee Manidipa M Modi Gyan Prakash GP Dubey Vikash Kumar VK

Chemical physics letters 20210219

SARS-CoV-2 has posed global challenge for healthcare due to COVID-19. The main protease (M<sup>pro</sup>) of this virus is considered as a major target for drug development efforts. In this work, we have used virtual screening approach with molecular dynamics simulations to identify high affinity and low molecular weight alternatives of boceprevir, a repurposed drug currently being evaluated against M<sup>pro</sup>. Out of 180 compounds screened, two boceprevir analogs (PubChem ID: 57841991 and ...[more]

PMID: 33623170

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Project description:Boceprevir is an HCV NSP3 inhibitor that was explored as a repurposed drug for COVID-19. It inhibits the SARS-CoV-2 main protease (MPro) and contains an α-ketoamide warhead, a P1 β-cyclobutylalanyl moiety, a P2 dimethylcyclopropylproline, a P3 tert-butylglycine, and a P4 N-terminal tert-butylcarbamide. By introducing modifications at all four positions, we synthesized 20 boceprevir-based MPro inhibitors including PF-07321332 and characterized their MPro inhibition potency in test tubes (in vitro) and 293T cells (in cellulo). Crystal structures of MPro bound with 10 inhibitors and cytotoxicity and antiviral potency of 4 inhibitors were characterized as well. Replacing the P1 site with a β-(S-2-oxopyrrolidin-3-yl)-alanyl (Opal) residue and the warhead with an aldehyde leads to high in vitro potency. The original moieties at P2, P3 and the P4 N-terminal cap positions in boceprevir are better than other tested chemical moieties for high in vitro potency. In crystal structures, all inhibitors form a covalent adduct with the MPro active site cysteine. The P1 Opal residue, P2 dimethylcyclopropylproline and P4 N-terminal tert-butylcarbamide make strong hydrophobic interactions with MPro, explaining high in vitro potency of inhibitors that contain these moieties. A unique observation was made with an inhibitor that contains a P4 N-terminal isovaleramide. In its MPro complex structure, the P4 N-terminal isovaleramide is tucked deep in a small pocket of MPro that originally recognizes a P4 alanine side chain in a substrate. Although all inhibitors show high in vitro potency, they have drastically different in cellulo potency to inhibit ectopically expressed MPro in human 293T cells. In general, inhibitors with a P4 N-terminal carbamide or amide have low in cellulo potency. This trend is reversed when the P4 N-terminal cap is changed to a carbamate. The installation of a P3 O-tert-butyl-threonine improves in cellulo potency. Three molecules that contain a P4 N-terminal carbamate were advanced to cytotoxicity tests on 293T cells and antiviral potency tests on three SARS-CoV-2 variants. They all have relatively low cytotoxicity and high antiviral potency with EC50 values around 1 μM. A control compound with a nitrile warhead and a P4 N-terminal amide has undetectable antiviral potency. Based on all observations, we conclude that a P4 N-terminal carbamate in a boceprevir derivative is key for high antiviral potency against SARS-CoV-2.

Dataset Information

Identification of high affinity and low molecular alternatives of boceprevir against SARS-CoV-2 main protease: A virtual screening approach.

Publications

Identification of high affinity and low molecular alternatives of boceprevir against SARS-CoV-2 main protease: A virtual screening approach.

Similar Datasets

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