Protein-ligand interactions from a quantum fragmentation perspective: The case of the SARS-CoV-2 main protease interacting with α-ketoamide inhibitors.
J Chem Phys
; 158(21)2023 Jun 07.
Article
en En
| MEDLINE
| ID: mdl-37272578
ABSTRACT
We present a hybrid, multi-method, computational scheme for protein/ligand systems well suited to be used on modern and forthcoming massively parallel computing systems. The scheme relies on a multi-scale polarizable molecular modeling, approach to perform molecular dynamics simulations, and on an efficient Density Functional Theory (DFT) linear scaling method to post-process simulation snapshots. We use this scheme to investigate recent α-ketoamide inhibitors targeting the main protease of the SARS-CoV-2 virus. We assessed the reliability and the coherence of the hybrid scheme, in particular, by checking the ability of MM and DFT to reproduce results from high-end ab initio computations regarding such inhibitors. The DFT approach enables an a posteriori fragmentation of the system and an investigation into the strength of interaction among identified fragment pairs. We show the necessity of accounting for a large set of plausible protease/inhibitor conformations to generate reliable interaction data. Finally, we point out ways to further improve α-ketoamide inhibitors to more strongly interact with particular protease domains neighboring the active site.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
SARS-CoV-2
/
COVID-19
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
J Chem Phys
Año:
2023
Tipo del documento:
Article
País de afiliación:
Francia