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J Mol Graph Model ; 110: 108042, 2022 01.
Article in English | MEDLINE | ID: covidwho-1517349


We have studied the non-covalent interaction between PF-07321332 and SARS-CoV-2 main protease at the atomic level using a computational approach based on extensive molecular dynamics simulations with explicit solvent. PF-07321332, whose chemical structure has been recently disclosed, is a promising oral antiviral clinical candidate with well-established anti-SARS-CoV-2 activity in vitro. The drug, currently in phase III clinical trials in combination with ritonavir, relies on the electrophilic attack of a nitrile warhead to the catalytic cysteine of the protease. Nonbonded interaction between the inhibitor and the residues of the binding pocket, as well as with water molecules on the protein surface, have been characterized using two different force fields and the two possible protonation states of the main protease catalytic dyad HIS41-CYS145. When the catalytic dyad is in the neutral state, the non-covalent binding is likely to be stronger. Molecular dynamics simulations seems to lend support for an inhibitory mechanism in two steps: a first non-covalent addition with the dyad in neutral form and then the formation of the thiolate-imidazolium ion pair and the ligand relocation for finalising the electrophilic attack.

COVID-19 , SARS-CoV-2 , Antiviral Agents/therapeutic use , Coronavirus 3C Proteases , Humans , Lactams , Leucine , Molecular Docking Simulation , Molecular Dynamics Simulation , Nitriles , Proline , Protease Inhibitors
Chem Phys Lett ; 750: 137489, 2020 Jul.
Article in English | MEDLINE | ID: covidwho-1025637


We have applied a computational strategy, using a combination of virtual screening, docking and molecular dynamics techniques, aimed at identifying possible lead compounds for the non-covalent inhibition of the main protease 3CLpro of the SARS-CoV2 Coronavirus. Based on the X-ray structure (PDB code: 6LU7), ligands were generated using a multimodal structure-based design and then docked to the monomer in the active state. Docking calculations show that ligand-binding is strikingly similar in SARS-CoV and SARS-CoV2 main proteases. The most potent docked ligands are found to share a common binding pattern with aromatic moieties connected by rotatable bonds in a pseudo-linear arrangement.

Int J Antimicrob Agents ; 56(2): 106055, 2020 Aug.
Article in English | MEDLINE | ID: covidwho-593424


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), similar to SARS-CoV and Middle East respiratory syndrome coronavirus (MERS-CoV), which belong to the same Betacoronavirus genus, induces severe acute respiratory disease that is a threat to human health. Since the outbreak of infection by SARS-CoV-2 began, which causes coronavirus disease 2019 (COVID-19), the disease has rapidly spread worldwide. Thus, a search for effective drugs able to inhibit SARS-CoV-2 has become a global pursuit. The 3C-like protease (3CLpro), which hydrolyses viral polyproteins to produce functional proteins, is essential for coronavirus replication and is considered an important therapeutic target for diseases caused by coronaviruses, including COVID-19. Many 3CLpro inhibitors have been proposed and some new drug candidates have achieved success in preclinical studies. In this review, we briefly describe recent developments in determining the structure of 3CLpro and its function in coronavirus replication and summarise new insights into 3CLpro inhibitors and their mechanisms of action. The clinical application prospects and limitations of 3CLpro inhibitors for COVID-19 treatment are also discussed.

Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Protease Inhibitors/therapeutic use , Viral Nonstructural Proteins/antagonists & inhibitors , Betacoronavirus , COVID-19 , Coronavirus 3C Proteases , Coronavirus Infections/virology , Cysteine Endopeptidases/chemistry , Humans , Molecular Structure , Pandemics , Pneumonia, Viral/virology , Protease Inhibitors/chemistry , SARS-CoV-2 , Viral Nonstructural Proteins/chemistry