The novel coronavirus disease 2019 (COVID‐19) caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) still has serious negative effects on health, social life, and economics. Recently, vaccines from various companies have been urgently approved to control SARS‐CoV‐2 infections. However, any specific antiviral drug has not been confirmed so far for regular treatment. An important target is the main protease (M pro ), which plays a major role in replication of the virus. In this study, Gaussian and residue network models are employed to reveal two distinct potential allosteric sites on M pro that can be evaluated as drug targets besides the active site. Then, Food and Drug Administration (FDA)‐approved drugs are docked to three distinct sites with flexible docking using AutoDock Vina to identify potential drug candidates. Fourteen best molecule hits for the active site of M pro are determined. Six of these also exhibit high docking scores for the potential allosteric regions. Full‐atom molecular dynamics simulations with MM‐GBSA method indicate that compounds docked to active and potential allosteric sites form stable interactions with high binding free energy (∆ G bind ) values. ∆ G bind values reach −52.06 kcal/mol for the active site, −51.08 kcal/mol for the potential allosteric site 1, and − 42.93 kcal/mol for the potential allosteric site 2. Energy decomposition calculations per residue elucidate key binding residues stabilizing the ligands that can further serve to design pharmacophores. This systematic and efficient computational analysis successfully determines ivermectine, diosmin, and selinexor currently subjected to clinical trials, and further proposes bromocriptine, elbasvir as M pro inhibitor candidates to be evaluated against SARS‐CoV‐2 infections.

We have investigated the pairs of rotational isomers for six 3-(o-aryl)-5-methyl-rhodanines (Z = H, F, Cl, Br, OH, and CH3) using NMR spectroscopy and density functional theory (DFT) calculations. Electron density topological and NBO analysis has demonstrated the importance of non-covalent interactions, characterised by (3, -1) bond critical points (BCPs), between the oxygen and sulfur atoms on the thiazolidine ring with the aryl substitutents in stabilizing the transition states. The energetic activation barriers to rotation have also been determined using computational results; rotational barriers for 3-(o-chlorophenyl)-5-methyl-rhodanine (3S) and 3-(o-tolyl)-5-methyl-rhodanine (6S) were determined experimentally based on NMR separation of the diastereoisomeric pairs, and the first-order rate constants used to derive the value of the rotational barrier from the Eyring equation.

The mechanism of ring-chain-ring tautomerization and the prominent effect of the solvent environment have been computationally investigated in an effort to explain the enantiomeric interconversion observed in 2-oxazolidinone derivatives, heterocyclic analogues of biphenyl atropisomers, which were isolated as single stable enantiomers and have the potential to be used as axially chiral catalysts. This study has shed light on the identity of the intermediate species involved in the ring-chain-ring tautomerization process as well as the catalytic effect of polar protic solvents. These mechanistic details will prove very useful in predicting and understanding ring-chain tautomeric equilibria in similar heterocyclic systems and will further enable experimentalists to devise appropriate experimental conditions in which axially chiral catalysts remain stable as single enantiomers.

The novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) still has serious negative effects on health, social life, and economics. Recently, vaccines from various companies have been urgently approved to control SARS-CoV-2 infections. However, any specific antiviral drug has not been confirmed so far for regular treatment. An important target is the main protease (Mpro), which plays a major role in replication of the virus. In this study, Gaussian and residue network models are employed to reveal two distinct potential allosteric sites on Mpro that can be evaluated as drug targets besides the active site. Then, FDA-approved drugs are docked to three distinct sites with flexible docking using AutoDock Vina to identify potential drug candidates. 14 best molecule hits for the active site of Mpro are determined. 6 of these also exhibit high docking scores for the potential allosteric regions. Full-atom molecular dynamics simulations with MM-GBSA method indicate that compounds docked to active and potential allosteric sites form stable interactions with high binding free energy (∆Gbind) values. ∆Gbind values reach -52.06 kcal/mol for the active site, -51.08 kcal/mol for the potential allosteric site 1, and -42.93 kcal/mol for the potential allosteric site 2. Energy decomposition calculations per residue elucidate key binding residues stabilizing the ligands that can further serve to design pharmacophores. This systematic and efficient computational analysis successfully determines ivermectine, diosmin and selinexor currently subjected to clinical trials, and further proposes bromocriptine, elbasvir as Mpro inhibitor candidates to be evaluated against SARS-CoV-2 infection

Pyridoxal 5-phosphate (PLP), the phosphorylated and the oxidized form of vitamin B6 is an organic cofactor. PLP forms a Schiff base with the ϵ-amino group of a lysine residue of PLP-dependent enzymes. γ-Aminobutyric acid (GABA) aminotransferase is a PLP-dependent enzyme that degrades GABA to succinic semialdehyde, while reduction of GABA concentration in the brain causes convolution besides several neurological diseases. The fluorine-containing substrate analogues for the inactivation of the GABA-AT are synthesized extensively in cases where the inactivation mechanisms involve HF elimination. Although two proposed mechanisms are present for the HF elimination, the details of the base-induced HF elimination are not well identified. In this density functional theory (DFT) study, fluorine-containing substrate analogue, 5-amino-2-fluorocyclohex-3-enecarboxylic acid, is particularly chosen in order to explain the details of the HF elimination reactions. On the other hand, the experimental studies revealed that aromatization competes with Michael addition mechanism in the presence of 5-amino-2-fluorocyclohex-3-enecarboxylic acid. The results allowed us to draw a conclusion for the nature of HF elimination, besides the elucidation of the mechanism preference for the inactivation mechanism. Furthermore, the solvent phase calculations carried out in this study ensure that the proton transfer steps should be assisted either by a water molecule or a base for lower activation energy barriers.