2. Academic Validation
  3. Estimation of Drug-Target Residence Times by τ-Random Acceleration Molecular Dynamics Simulations

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

  • J Chem Theory Comput. 2018 Jul 10;14(7):3859-3869. doi: 10.1021/acs.jctc.8b00230.
Daria B Kokh 1,  Marta Amaral 2 3,  Joerg Bomke 4,  Ulrich Grädler 2,  Djordje Musil 2,  Hans-Peter Buchstaller 5,  Matthias K Dreyer 6,  Matthias Frech 2,  Maryse Lowinski 7,  Francois Vallee 7,  Marc Bianciotto 7,  Alexey Rak 7,  Rebecca C Wade 1 8 9
Affiliations

Affiliations

  • 1 Molecular and Cellular Modeling Group , Heidelberg Institute for Theoretical Studies , Heidelberg 69118 , Germany.
  • 2 Molecular Interactions and Biophysics , Merck KGaA , Darmstadt 64293 , Germany.
  • 3 Instituto de Biologia Experimental e Tecnológica, Oeiras 2780-157 , Portugal.
  • 4 Molecular Pharmacology , Merck KGaA , Darmstadt 64293 , Germany.
  • 5 Medicinal Chemistry , Merck KGaA , Darmstadt 64293 , Germany.
  • 6 R&D Integrated Drug Discovery , Sanofi-Aventis Deutschland GmbH , Frankfurt am Main 65926 , Germany.
  • 7 Integrated Drug Discovery , Sanofi R&D , Vitry-sur-Seine F-94403 , France.
  • 8 Center for Molecular Biology (ZMBH), DKFZ-ZMBH Alliance , Heidelberg University , Heidelberg 69120 , Germany.
  • 9 Interdisciplinary Center for Scientific Computing (IWR) , Heidelberg University , Heidelberg 69120 , Germany.
PMID: 29768913 DOI: 10.1021/acs.jctc.8b00230
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.

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