Investigação de Variações de Três Fármacos Comerciais como Candidatos a Inibidores da Proteína Spike do SARS-CoV-2

Abstract

The present work aimed to use molecular mechanics, dynamics and electronic structure calcu- lation techniques in order to stablish a drug discovery protocol, which was tested for the re- search of 2053 analog drugs with possibility of inhibiting SARS-CoV-2’s spike protein. It was generated drug candidates based on three existant ones: baloxavir acid, oseltamivir and zanamivir and the structures of 45 organic ligands added to specific positions of each drug. The best docked structure in regard to affinity energy and proximity to the protein’s active site, was submited to molecular dynamics in order to optimize system’s atomic positions. A total of 100 ns trajectory was obtained so it could be passed on to a quantum mechanics calcu- lation, TDDFT level, in search of more precise informations regarding the drug interaction with the aminoacid residues nearby. The best candidate was a variant of baloxavir acid to which was added a bromine atom, but, the excited states results showed a little probability of electronic movement for the availed system. Such a result emphasizes the need of conducting more robust experiments to filter preliminary results from molecular dockings, because it was possible to detect the low sucess chance of the cited mutant even after it’s preliminary suc- cess. Hence, taking into account the computational cost of all the techniques, the protocol test shows that it is possible to eliminate false positives from molecular dockings by the use of more consistent techniques such as molecular dynamics.