期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 23, 期 22, 页码 -出版社
MDPI
DOI: 10.3390/ijms232213972
关键词
SARS-CoV-2; nsp16; nsp10; SAM analog; inhibition mechanism; MD simulations; binding free energy
资金
- National Council for Scientific and Technological Development [88887.712684/2022-00, 88887.598552/2021-00]
- CAPES [2013/08293-7]
- FAPESP
This study evaluates inhibitors of MTases enzymes for SARS-CoV-2 and provides structural and energetic analysis using computational modeling techniques. The most potent inhibitor shows lower binding free energy and higher potency than known inhibitors. Additionally, analysis of cell permeability suggests that the inhibitors suffer from poor cell permeability.
Methyltransferases (MTases) enzymes, responsible for RNA capping into severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are emerging important targets for the design of new anti-SARS-CoV-2 agents. Here, analogs of S-adenosylmethionine (SAM), obtained from the bioisosteric substitution of the sulfonium and amino acid groups, were evaluated by rigorous computational modeling techniques such as molecular dynamics (MD) simulations followed by relative binding free analysis against nsp16/nsp10 complex from SARS-CoV-2. The most potent inhibitor (2a) shows the lowest binding free energy (-58.75 Kcal/mol) and more potency than Sinefungin (SFG) (-39.8 Kcal/mol), a pan-MTase inhibitor, which agrees with experimental observations. Besides, our results suggest that the total binding free energy of each evaluated SAM analog is driven by van der Waals interactions which can explain their poor cell permeability, as observed in experimental essays. Overall, we provide a structural and energetic analysis for the inhibition of the nsp16/nsp10 complex involving the evaluated SAM analogs as potential inhibitors.
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