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J Med Chem ; 65(19): 13013-13028, 2022 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-36178213

RESUMO

The accurate prediction of protein-ligand binding affinity belongs to one of the central goals in computer-based drug design. Molecular dynamics (MD)-based free energy calculations have become increasingly popular in this respect due to their accuracy and solid theoretical basis. Here, we present a combined study which encompasses experimental and computational studies on two series of factor Xa ligands, which enclose a broad chemical space including large modifications of the central scaffold. Using this integrated approach, we identified several new ligands with different heterocyclic scaffolds different from the previously identified indole-2-carboxamides that show superior or similar affinity. Furthermore, the so far underexplored terminal alkyne moiety proved to be a suitable non-classical bioisosteric replacement for the higher halogen-π aryl interactions. With this challenging example, we demonstrated the ability of the MD-based non-equilibrium free energy calculation approach for guiding crucial modifications in the lead optimization process, such as scaffold replacement and single-site modifications at molecular interaction hot spots.


Assuntos
Fator Xa , Proteínas , Alcinos , Fator Xa/metabolismo , Halogênios , Indóis , Ligantes , Simulação de Dinâmica Molecular , Ligação Proteica , Proteínas/metabolismo , Termodinâmica
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