Bioisosterismo aplicado para execução de ancoragem molecular contra alvos essenciais do SARS-CoV-2

Abstract

SARS-CoV-2 cysteine proteases, namely main protease (Mpro) and papain-like protease (PLpro) are essential non-structural proteins due to their role in the formation of the virus multiple enzymatic replication-transcription complex (RTC). As a result, these functional proteins are extremely relevant targets in the development of a new drug candidate to fight COVID-19. In this sense, to date, nirmatrelvir is the only drug acting as a covalent Mpro inhibitor that has been approved by regulatory agencies around the world for emergency use. In addition, a novel drug, acting as a non-covalent Mpro inhibitor, namely ensitrelvir, has been approved only in Japan for emergency use. However, a recent paper published by Iketani and collaborators in early November 2022 argues that SARS-CoV-2 might have already acquired resistance to nirmaltrevir and ensitrelvir via several pathways evinced through in vitro studies. Based on this fact and guided by the bioisosterism strategy, the present work has selected 126 out of 1050 ligands, including both approved and investigational drugs, from DrugBank website. Subsequently, 831 chemical analogs containing bioisosteres, some of which became structurally simplified, were created using the MB-Isoster software. Also, based on IC50 results generated from in vitro experiments of other researchers, 2 control ligands belonging to the subclass of non-covalent inhibitors were chosen for both Mpro and PLpro. Ionization states at pH 7.4 of all molecules as well as of both enzymes were then applied, and molecular docking simulations were performed using AutoDock Vina. The results of the most promising analogs, as well as of their precursors and control ligands, were analyzed using the Pymol and Discovery Studio programs. Finally, a study of their physicochemical properties, along with aspects of druggability, such as structural alerts and synthetic accessibility, and ADMET profiles were carried out through SwissADME and ADMETlab 2.0 platforms. The promising results obtained with the molecules encoded as DB00549_BI_005, DB04868_BI_003, DB11984_BI_002, DB12364_BI_006 and DB12805_BI_004 must be confirmed by molecular dynamics studies, followed by in vitro and in vivo empirical tests that ratify the advocated in-silico results.