Deconstructing allostery by computational assessment of the binding determinants of allosteric PTP1B modulators.

ABSTRACT: Fragment-based drug discovery is an established methodology for finding hit molecules that can be elaborated into lead compounds. However it is currently challenging to predict whether fragment hits that do not bind to an orthosteric site could be elaborated into allosteric modulators, as in these cases binding does not necessarily translate into a functional effect. We propose a workflow using Markov State Models (MSMs) with steered molecular dynamics (sMD) to assess the allosteric potential of known binders. sMD simulations are employed to sample protein conformational space inaccessible to routine equilibrium MD timescales. Protein conformations sampled by sMD provide starting points for seeded MD simulations, which are combined into MSMs. The methodology is demonstrated on a dataset of

SUBMITTER: Hardie A 

PROVIDER: S-EPMC10272186 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature