Estimation of Drug-Target Residence Times by τ-Random Acceleration Molecular Dynamics Simulations

2018/05/16 by Daria B. Kokh, Marta Amaral, Joerg Bomke +10 · 1 voice · 5 citations
Biochemistry, Genetics and Molecular Biology · Computer Science · #Computational Drug Discovery Methods #Heat shock proteins research #Protein Structure and Dynamics

paper · pdf · doi:10.1021/acs.jctc.8b00230

openalex publication_date 2018/05/16 · openalex created_date 2025/10/10 · openalex updated_date 2026/07/30

Abstract

Drug-target residence time (τ), one of the main determinants of drug efficacy, remains highly challenging to predict computationally and, therefore, is usually not considered in the early stages of drug design. Here, we present an efficient computational method, τ-random acceleration molecular dynamics (τRAMD), for the ranking of drug candidates by their residence time and obtaining insights into ligand-target dissociation mechanisms. We assessed τRAMD on a data set of 70 diverse drug-like ligands of the N-terminal domain of HSP90α, a pharmaceutically important target with a highly flexible binding site, obtaining computed relative residence times with an accuracy of about 2.3τ for 78% of the compounds and less than 2.0τ within congeneric series. Analysis of dissociation trajectories reveals features that affect ligand unbinding rates, including transient polar interactions and steric hindrance. These results suggest that τRAMD will be widely applicable as a computationally efficient aid to improving drug residence times during lead optimization.

Citations

• A well-behaved electrostatic potential based method using charge restraints for deriving atomic charges: the RESP model
• Towards the comprehensive, rapid, and accurate prediction of the favorable tautomeric states of drug-like molecules in aqueous solution
• Jaguar: A high‐performance quantum chemistry software program with strengths in life and materials sciences
• Epik: a software program for pK a prediction and protonation state generation for drug-like molecules
• Development and testing of a general amber force field

Cited by

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• A discard-and-restart MD algorithm for the sampling of protein intermediate states

Discussions

• To test how interface opening plays a role in ADP release, Josh performed tRAMD(doi.org/10.1021/acs....), which is a technique that predicts relative release rates. He found that the half-off rate for [bsky, 0 points, 1 comments]