Identification of a novel dual-target scaffold for 3CLpro and RdRp proteins of SARS-CoV-2 using 3D-similarity search, molecular docking, molecular dynamics and ADMET evaluation

Abstract

The new SARS-CoV-2 coronavirus is the causative agent of the COVID-19 pandemic outbreak that affected whole the world with more than 6 million confirmed cases and over 370,000 deaths. At present, there are no effective treatments or vaccine for this disease, which constitutes a serious global health crisis. As the pandemic still spreading around the globe, it is of interest to use computational methods to identify potential inhibitors for the virus. The crystallographic structures of 3CLpro (PDB: 6LU7) and RdRp (PDB 6ML7) were used in virtual screening of 50000 chemical compounds obtained from the CAS Antiviral COVID19 database using 3D-similarity search and standard molecular docking followed by ranking and selection of compounds based on their binding affinity, computational techniques for the sake of details on the binding interactions, absorption, distribution, metabolism, excretion, and toxicity prediction; we report three 4-(morpholin-4-yl)-1,3,5-triazin-2-amine derivatives; two compounds (2001083-68-5 and 2001083-69-6) with optimal binding features to the active site of the main protease and one compound (833463-19-7) with optimal binding features to the active site of the polymerase for further consideration to fight COVID-19. The structural stability and dynamics of lead compounds at the active site of 3CLpro and RdRp were examined using molecular dynamics (MD) simulation. Essential dynamics demonstrated that the three complexes remain stable during simulation of 20 ns, which may be suitable candidates for further experimental analysis. As the identified leads share the same scaffold, they may serve as promising leads in the development of dual 3CLpro and RdRp inhibitors against SARS-CoV-2.

Inhibitor binding influences the protonation states of histidines in SARS-CoV-2 main protease

“…Nevertheless, additional optimization to improve their potency is desirable for both compounds. Previous simulations of M pro used either Pymol, H++ webserver, or Protein Preparation Wizard from Schrödinger in order to assign hydrogens to the histidines and to Cys145 [22][23][24][25][26][27][28] . To compare automatic protonation assignment with our results, we have examined the protonation states obtained from the H++ server and from Protein Preparation Wizard at pH 7.0 (Table S5) 63,73 .…”

Inhibitor binding influences the protonation states of histidines in SARS-CoV-2 main protease

“…Since the release of SARS-CoV-2 M pro structures in apo and inhibitor-bound states, multiple MD simulation and docking studies of this enzyme have already been published. [22][23][24][25][26][27][28] Although a precise determination of the specific protonation states of Cys145 and several histidines in M pro in this pH-sensitive enzyme will be critical to effective and robust computational drug design efforts, these protonation states have not been unequivocally determined.…”

Orientation of immobilized antigens on common surfaces by a simple computational model: Exposition of SARS-CoV-2 Spike protein RBD epitopes

“…Our results suggest that very simple modelling approaches can provide significant hints towards rationally orienting antigens in a way to maximize the exposition of epitopes, and therefore help in the initial moments of the design of conjugates for immunologic applications, when a rapid response to emergency is vital. This is also testified by the emergence of theoretical modelling of several molecular aspects of viral infection and inhibition mechanisms [ [71] , [72] , [73] , [74] , [75] , [76] ]. Overall, the expected short-time impact of our work is to provide guidelines to avoid the experimental exploration of immobilization pathways that are less promising.…”