Relative free-energy calculations for scaffold hopping-type transformations with an automated RE-EDS sampling procedure.

Publisher: Springer Country of Publication: Netherlands NLM ID: 8710425 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1573-4951 (Electronic) Linking ISSN: 0920654X NLM ISO Abbreviation: J Comput Aided Mol Des Subsets: MEDLINE

Publication: Amsterdam : Springer
Original Publication: Leiden, The Netherlands : ESCOM, [c1987-

Molecular Dynamics Simulation*; Entropy ; Ligands ; Thermodynamics

The calculation of relative free-energy differences between different compounds plays an important role in drug design to identify potent binders for a given protein target. Most rigorous methods based on molecular dynamics simulations estimate the free-energy difference between pairs of ligands. Thus, the comparison of multiple ligands requires the construction of a "state graph", in which the compounds are connected by alchemical transformations. The computational cost can be optimized by reducing the state graph to a minimal set of transformations. However, this may require individual adaptation of the sampling strategy if a transformation process does not converge in a given simulation time. In contrast, path-free methods like replica-exchange enveloping distribution sampling (RE-EDS) allow the sampling of multiple states within a single simulation without the pre-definition of alchemical transition paths. To optimize sampling and convergence, a set of RE-EDS parameters needs to be estimated in a pre-processing step. Here, we present an automated procedure for this step that determines all required parameters, improving the robustness and ease of use of the methodology. To illustrate the performance, the relative binding free energies are calculated for a series of checkpoint kinase 1 inhibitors containing challenging transformations in ring size, opening/closing, and extension, which reflect changes observed in scaffold hopping. The simulation of such transformations with RE-EDS can be conducted with conventional force fields and, in particular, without soft bond-stretching terms.
(© 2021. The Author(s).)

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200021-178762 Switzerland SNSF_ Swiss National Science Foundation

Keywords: Enveloping distribution sampling; Free energy calculation; Molecular dynamics; Protein-ligand binding; Replica exchange

0 (Ligands)

Date Created: 20220103 Date Completed: 20220502 Latest Revision: 20220502

20240829

PMC8907147

10.1007/s10822-021-00436-z

34978000