Computational prediction of potential inhibitors for SARS-COV-2 main protease based on machine learning, docking, MM-PBSA calculations, and metadynamics

被引:9
作者
Gomes, Isabela de Souza [1 ]
Santana, Charles Abreu [2 ,3 ]
Marcolino, Leandro Soriano [4 ]
Franca de Lima, Leonardo Henrique [5 ]
de Melo-Minardi, Raquel Cardoso [2 ,3 ]
Dias, Roberto Sousa [6 ]
de Paula, Sergio Oliveira [7 ]
Silveira, Sabrina de Azevedo [1 ]
机构
[1] Univ Fed Vicosa, Dept Comp Sci, Vicosa, MG, Brazil
[2] Univ Fed Minas Gerais, Dept Biochem & Immunol, Belo Horizonte, MG, Brazil
[3] Univ Fed Minas Gerais, Dept Comp Sci, Belo Horizonte, MG, Brazil
[4] Univ Lancaster, Sch Comp & Commun, Lancaster, England
[5] Univ Fed Sao Joao Rei, Dept Exact & Biol Sci, Sete Lagoas Campus, Sete Lagoas, MG, Brazil
[6] Univ Fed Vicosa, Dept Gen Biol, Vicosa, MG, Brazil
[7] Univ Fed Vicosa, Dept Microbiol, Vicosa, MG, Brazil
关键词
MOLECULAR-DYNAMICS; DRUG DISCOVERY; FORCE-FIELD; GROMACS; SOFTWARE; DESIGN; TOOL;
D O I
10.1371/journal.pone.0267471
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
The development of new drugs is a very complex and time-consuming process, and for this reason, researchers have been resorting heavily to drug repurposing techniques as an alternative for the treatment of various diseases. This approach is especially interesting when it comes to emerging diseases with high rates of infection, because the lack of a quickly cure brings many human losses until the mitigation of the epidemic, as is the case of COVID-19. In this work, we combine an in-house developed machine learning strategy with docking, MM-PBSA calculations, and metadynamics to detect potential inhibitors for SARS-COV-2 main protease among FDA approved compounds. To assess the ability of our machine learning strategy to retrieve potential compounds we calculated the Enrichment Factor of compound datasets for three well known protein targets: HIV-1 reverse transcriptase (PDB 4B3P), 5-HT2A serotonin receptor (PDB 6A94), and H1 histamine receptor (PDB 3RZE). The Enrichment Factor for each target was, respectively, 102.5, 12.4, 10.6, which are considered significant values. Regarding the identification of molecules that can potentially inhibit the main protease of SARS-COV-2, compounds output by the machine learning step went through a docking experiment against SARS-COV-2 M-pro. The best scored poses were the input for MM-PBSA calculations and metadynamics using CHARMM and AMBER force fields to predict the binding energy for each complex. Our work points out six molecules, highlighting the strong interaction obtained for M-pro-mirabegron complex. Among these six, to the best of our knowledge, ambenonium has not yet been described in the literature as a candidate inhibitor for the SARS-COV-2 main protease in its active pocket.
引用
收藏
页数:20
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