Cosolvent Simulations with Fragment-Bound Proteins Identify Hot Spots to Direct Lead Growth.

ABSTRACT: In drug design, chemical groups are sequentially added to improve a weak-binding fragment into a tight-binding lead molecule. Often, the direction to make these additions is unclear, and there are numerous chemical modifications to choose. Lead development can be guided by crystal structures of the fragment-bound protein, but this alone is unable to capture structural changes like closing or opening of the binding site and any side-chain movements. Accounting for adaptation of the site requires a dynamic approach. Here, we use molecular dynamics calculations of small organic solvents with protein-fragment pairs to reveal the nearest "hot spots". These close hot spots show the direction to make appropriate additions and suggest types of chemical modifications that could improve binding affi

SUBMITTER: Lal Gupta P 

PROVIDER: S-EPMC10262261 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature