Eliglustat for COVID-19

Abstract The global pandemic caused by SARS-CoV-2 has underscored the critical necessity for effective antiviral therapies. The viral main protease (Mpro), crucial for viral replication, has emerged as a promising therapeutic target. In the present study, the inhibitory potential of ten drug-like compounds (KL1-KL10), designed as derivatives of the parent inhibitor K36, against Mpro, has been computationally investigated. To elucidate the binding affinities and interactions of the suggested drugs with the Mpro active site, molecular docking and molecular dynamics (MD) simulations till 500 nanoseconds have been applied. Our results revealed that many suggested inhibitors exhibited enhanced binding affinities compared to the parent inhibitor K36. Among these, KL7 displayed the most favourable binding characteristics, with a docking score of -13.54 and MM-PBSA binding energy of -34.57 kJ/mol, surpassing that of K36. Molecular dynamics simulations demonstrated persistent binding of these compounds to Mpro, with RMSD values ranging from 0.5 to 2.0 nm, suggesting their potential as effective inhibitors. These findings suggest that the proposed ligands hold promise as potential scaffolds for developing potent antiviral drugs against COVID-19.

AbstractIdentification of host factors contributing to replication of viruses and resulting disease progression remains a promising approach for development of new therapeutics. Here, we evaluated 6710 clinical and preclinical compounds targeting 2183 host proteins by immunocytofluorescence-based screening to identify SARS-CoV-2 infection inhibitors. Computationally integrating relationships between small molecule structure, dose-response antiviral activity, host target and cell interactome networking produced cellular networks important for infection. This analysis revealed 389 small molecules, >12 scaffold classes and 813 host targets with micromolar to low nanomolar activities. From these classes, representatives were extensively evaluated for mechanism of action in stable and primary human cell models, and additionally against Beta and Delta SARS-CoV-2 variants and MERS-CoV. One promising candidate, obatoclax, significantly reduced SARS-CoV-2 viral lung load in mice. Ultimately, this work establishes a rigorous approach for future pharmacological and computational identification of novel host factor dependencies and treatments for viral diseases.