Identification of saquinavir as a potent inhibitor of dimeric SARS-CoV2 main protease through MM/GBSA

Abstract

Among targets selected for studies aimed at identifying potential inhibitors against COVID-19, SARS-CoV2 main proteinase (M^pro) is highlighted. M^pro is indispensable for virus replication and is a promising target of potential inhibitors of COVID-19. Recently, monomeric SARS-CoV2 M^pro, drug repurposing, and docking methods have facilitated the identification of several potential inhibitors. Results were refined through the assessment of dimeric SARS-CoV2 M^pro, which represents the functional state of enzyme. Docking and molecular dynamics (MD) simulations combined with molecular mechanics/generalized Born surface area (MM/GBSA) studies indicated that dimeric M^pro most significantly impacts binding affinity tendency compared with the monomeric state, which suggests that dimeric state is most useful when performing studies aimed at identifying drugs targeting M^pro. In this study, we extend previous research by performing docking and MD simulation studies coupled with an MM/GBSA approach to assess binding of dimeric SARS-CoV2 M^pro to 12 FDA-approved drugs (darunavir, indinavir, saquinavir, tipranavir, diosmin, hesperidin, rutin, raltegravir, velpatasvir, ledipasvir, rosuvastatin, and bortezomib), which were identified as the best candidates for the treatment of COVID-19 in some previous dockings studies involving monomeric SARS-CoV2 M^pro. This analysis identified saquinavir as a potent inhibitor of dimeric SARS-CoV2 M^pro; therefore, the compound may have clinical utility against COVID-19. Graphical abstract.

Keywords: Docking; MD simulations; Protease; SARS-CoV2.

Graphical abstract

Fig. 1

Interactions between complexes comprised of ligands and dimeric SARS-CoV2 M^pro. Peptide-like inhibitor N3 bound to subunits 1 (a) and 2 (b), darunavir bound to subunits 1 (c) and 2 (d), and indinavir bound to subunits 1 (e) and 2 (f) of dimeric SARS-CoV2 M^pro are shown. Each complex resembles the most populated complex generated via a molecular docking simulation. The receptor is shown in the green cartoon representation, interacting residues are shown with green sticks, and the ligand is shown using a ball and stick representation. The figure was constructed with PyMOL 0.99rc6 [27]

Fig. 2

Interaction map of ligand and dimeric SARS-CoV2 M^pro complex formation. Saquinavir bound to subunits 1 (a) and 2 (b), tipranavir bound to subunits 1 (c) and 2 (d), and diosmin bound to subunits 1 (e) and 2 (f) of dimeric SARS-CoV2 M^pro are shown

Fig. 3

Interaction map of ligand and dimeric SARS-CoV3 M^pro complex formation. Hesperidin coupled to subunits 1 (a) and 2 (b), raltegravir bound to subunits 1 (c) and 2 (d), and velpatasvir bound subunits 1 (e) and 2 (f) of dimeric SARS-CoV2 M^PRO

Fig. 4

Interaction map of ligand and dimeric SARS-CoV2 M^pro. Ledipasvir bound subunit 1 (a), rosuvastatin bound to subunits 1 (c) and 2 (d), bortezomib bound subunits 1 (e) and 2 (f) of dimeric SARS-CoV2 M^pro