In Search of Non-covalent Inhibitors of SARS-CoV-2 Main Protease: Computer Aided Drug Design Using Docking and Quantum Chemistry

Abstract

Two stages virtual screening of a database containing several thousand low molecular weight organic compounds is performed with the goal to find inhibitors of SARS-CoV-2 main protease. Overall near 41000 different 3D molecular structures have been generated from the initial molecules taking into account several conformers of most molecules. At the first stage the classical SOL docking program is used to determine most promising candidates to become inhibitors. SOL employs the MMFF94 force field, the genetic algorithm (GA) of the global energy optimization, takes into account the desolvation effect arising upon protein-ligand binding and the internal stress energy of the ligand. Parameters of GA are selected to perform the meticulous global optimization, and for docking of one ligand several hours on one computing core are needed on the average. The main protease model is constructed on the base of the protein structure from the Protein Data Bank complex 6W63. More than 1000 ligands structures have been selected for further postprocessing. The SOL score values of these ligands are more negative than the threshold of −6.3 kcal/mol obtained for the native X77 ligand docking. Subsequent calculation of the protein-ligand binding enthalpy by the PM7 quantum-chemical semiempirical method with COSMO solvent model have narrowed down the number of best candidates. Finally, the diverse set of 20 most perspective candidates for the in vitro validation are selected.

New Chemicals Suppressing SARS-CoV-2 Replication in Cell Culture

“…Relying upon results of docking and quantum chemical calculations of the protein–ligand binding enthalpy, the analysis of the docked ligand poses in the protein active site, and providing the chemical diversity of the ligands, we selected a series of compounds for the first experimental testing [ 38 ]. All these ligands blocked the catalytic dyad of the SARS-CoV-2 M in their docked conformations.…”

“…The calculated and measured characteristics of the three active compounds ( 3a , 6a , 9a ) determined among the first set of 18 compounds selected for experimental testing [ 38 ] are presented in Table 1 . These characteristics are: the estimate of the free energy of protein–ligand binding calculated by SOL (SOL score), the protein–ligand binding enthalpy , as well as the 50% effective concentrations (EC ) of the compounds that inhibit the viral replication the cell culture and the selectivity index .…”

“…They had no missed residues or atoms, and their resolution was better than 2.2 Å. The atomistic models of M were prepared using these structures (details can be found in [ 38 ]) and the docking of native ligands was performed using the SOL docking program [ 6 , 56 ]. The docking of the native ligand into the M model constructed using the 5R7Z structure was unsuccessful: the docked and crystallized native ligand poses differed by RMSD = 7 Å.…”

“…The PM7+COSMO energy of the unbound protein was calculated for the conformation used for docking, and for the unbound ligand, the energy of the ligand conformation with the lowest energy calculated by the PM7+COSMO method was used. The enthalpy of binding was calculated as the difference between these three PM7/COSMO energies: the energies of the unbound protein and unbound ligand were subtracted from the energy of the complex [ 38 ]. The MOPAC program and the PM7 method were chosen for these calculations because MOPAC could process protein–ligand complexes with sufficient speed due to the use of the localized molecular orbital method implemented in the MOZYME module, and PM7 described dispersion interactions as well as hydrogen and halogen bonds with an accuracy approaching that obtained by DFT methods.…”

Interaction of the new inhibitor paxlovid (PF-07321332) and ivermectin with the monomer of the main protease SARS-CoV-2: A volumetric study based on molecular dynamics, elastic networks, classical thermodynamics and SPT

“…On the other hand, the controversy increases because ivermectin has been included in clinical trials that have shown promising results ( Carvallo and Hirsch, 2020 ) ( https://clinicaltrials.gov/ct2/show/NCT04425863 - ClinicalTrials.gov Identifier: NCT04425863) and in collective reviews of multiple efforts that have suggested that ivermectin may have a prophylactic effect and would be a strong candidate for clinical trials to treat SARS-CoV-2 ( Low et al, 2022 ), as also observed in systematic reviews and meta-analyses of randomized clinical trial studies ( Hariyanto et al, 2022 ). In addition, general descriptions of the possible mechanisms of action have been provided based on experimental and computational studies that have suggested a multi-target mechanism of ivermectin against SARS-CoV-2 ( Tang and Dill, 1998 , Tang and Kaneko, 2020 ).…”