The SARS-CoV-2 3CL protease (3CLpro) shows a high similarity with 3CL proteases of other beta-coronaviruses, such as SARS and MERS. It is the main enzyme involved in generating various non-structural proteins that are important for viral replication and is one of the most important proteins responsible for SARS-CoV-2 virulence. In this study, we have conducted an ensemble docking of molecules from the DrugBank database using both the crystallographic structure of the SARS-CoV-2 3CLpro, as well as five conformations obtained after performing a cluster analysis of a 300 ns molecular dynamics (MD) simulation. This procedure elucidated the inappropriateness of the active site for non-covalent inhibitors, but it has also shown that there exists an additional, more favorable, allosteric binding site, which could be a better target for non-covalent inhibitors, as it could prevent dimerization and activation of SARS-CoV-2 3CLpro. Two such examples are radotinib and nilotinib, tyrosine kinase inhibitors already in use for treatment of leukemia and which binding to the newly found allosteric binding site was also confirmed using MD simulations. Communicated by Ramaswamy H. Sarma

During metastasis, cancer cells transcend from primary site to normal cells area upon attaining epithelial to mesenchymal transition (EMT) causing malignant cancer disease. Increased expression of TGF-β and its receptor ALK5 is an important hallmark of malignant cancer. In the present study, efficacy of curcumin and its analogues as inhibitors of ALK5 (TGFβR-I) receptor was evaluated using in silico approaches. A total of 142 curcumin analogues and curcumin were retrieved from peer reviewed literature and constructed a combinatorial library. Further their drug-likeness was assessed using Molinspiration, cheminformatics and preADMET online servers. The interaction of 142 curcumin analogues and curcumin with ALK5 receptor was studied using Autodock Vina. This study revealed six curcumin analogues as promising ALK5 inhibitors with significant binding energy and H-bonding interaction.

The complementarity principle is a well-established concept in the field of chemistry and biology. This concept is widely studied as the lock-and-key relationship between two structures, such as enzyme and ligand interactions. These interactions are based on the overlap of electron clouds between two structures. In this study, a mathematical relation determining complementarity of intermolecular contacts in terms of overlaps of electron clouds was examined using a quantum orbital-free AlteQ method developed in-house for 64 EGFR–ligand complexes with experimentally measured binding affinity data. A very high correlation was found between the overlap of ligand and enzyme electron clouds and the calculated terms, providing a good basis for prognosis of bioactivity and for molecular docking studies.

Background: The SARS-CoV-2 3CLpro is one of the primary targets for designing new and repurposing known drugs. Methodology: A virtual screening of molecules from the Natural Product Atlas was performed, followed by molecular dynamics simulations of the most potent inhibitor bound to two conformations of the protease and into two binding sites. Conclusion: Eight molecules with appropriate ADMET properties are suggested as potential inhibitors. The greatest benefit of this study is the demonstration that these ligands can bind in the catalytic site but also to the groove between domains II and III, where they interact with a series of residues which have an important role in the dimerization and the maturation process of the enzyme.

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