Searching and designing potential inhibitors for SARS-CoV-2 Mpro from natural sources using atomistic and deep-learning calculations

Abstract

The hybrid DeepFrag/atomistic simulation approach could lead to a new scheme for developing SARS-CoV-2 3CLpro/Mpro inhibitors.

Upgrading nirmatrelvir to inhibit SARS-CoV-2 Mpro via DeepFrag and free energy calculations

“…DeepFrag calculations were designed to predict the structural change of the inhibitor that may enhance the ligand-binding affinity [ 34 , 35 ]. In particular, the ML model was successfully applied to the SARS-CoV-2 Mpro + inhibitor [ 38 ]. The ligand-binding affinity was then confirmed via FPL simulations [ 38 ], which revealed a correlation coefficient with the respective experiment of [ 32 ].…”

“…In particular, the ML model was successfully applied to the SARS-CoV-2 Mpro + inhibitor [ 38 ]. The ligand-binding affinity was then confirmed via FPL simulations [ 38 ], which revealed a correlation coefficient with the respective experiment of [ 32 ]. The hybrid approaches were thus utilized to modify the structure of nirmatrelvir, which may lead to a novel compound forming stronger binding affinity to the protease.…”

“…Among these, the inhibitor atoms were designated to estimate that the ligand-binding affinity can be enhanced if they are replaced by another chemical group. A probable modification was kept if the score of the DeepFrag model was larger than 0.90 [ 38 ].

Fig.

…”

A High-throughput screening system for SARS-CoV-2 entry inhibition, syncytia formation and cell toxicity

“…Streptonigrin tetracyclic aminoquinoline-5,8 dione is an antitumor antibiotic and a previous screening against SARS-CoV-2 nsp15 endoribonuclease identi ed as positive hit [23]. Scillaren A, is a cardiac glycoside derived from Drimia species [24] and in silico studies reported to have SARS CoV-2 Mpro binding a nities [25]. Proscillaridin, is a cardiac glycoside isolated from Drimia maritima, an anticancer drug that inhibits DNA topoisomerase I and II [26].…”

A high-throughput screening system for SARS-CoV-2 entry inhibition, syncytia formation and cell toxicity

“…Streptonigrin tetracyclic aminoquinoline-5,8 dione is an antitumor antibiotic, and previous screening against SARS-CoV-2 nsp15 endoribonuclease identified it as a positive hit [ 24 ]. Scillaren A is a cardiac glycoside derived from Drimia species [ 25 ] and in silico studies have been reported to have SARS-CoV-2 Mpro binding affinities [ 26 ]. In our present study, Scillaren A inhibits pseudovirion infection and Spike S1 binding.…”