Entropy driven cooperativity effect in multi-site drug optimization targeting SARS-CoV-2 papain-like protease.

ABSTRACT: Papain-like protease (PLpro), a non-structural protein encoded by SARS-CoV-2, is an important therapeutic target. Regions 1 and 5 of an existing drug, GRL0617, can be optimized to produce cooperativity with PLpro binding, resulting in stronger binding affinity. This work investigated the origin of the cooperativity using molecular dynamics simulations combined with the interaction entropy (IE) method. The regions' improvement exhibits cooperativity by calculating the binding free energies between the complex of PLpro-inhibitor. The thermodynamic integration method further verified the cooperativity generated in the drug improvement. To further determine the specific source of cooperativity, enthalpy and entropy in the complexes were calculated using molecular mechanics/generalized Born sur

SUBMITTER: Duan L 

PROVIDER: S-EPMC11072831 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature