Accelerating Alchemical Free Energy Prediction Using a Multistate Method: Application to Multiple Kinases
OPEN ACCESS
Loading...
Author / Producer
Date
2023-09-14
Publication Type
Working Paper
ETH Bibliography
yes
Citations
Altmetric
OPEN ACCESS
Data
Abstract
lchemical free-energy methods based on molecular dynamics (MD) simulations have become important tools to identify modifications of small organic molecules that improve their protein binding affinity during lead optimization. The routine application of pairwise free-energy methods to rank potential binders from best to worst is impacted by the combinatorial increase of calculations to perform when the number of molecules to assess grows. To address this fundamental limitation, our group has developed replica-exchange enveloping distribution sampling (RE-EDS), a pathway-independent multistate method, enabling the calculation of alchemical free-energy differences between multiple ligands (N > 2) from a single MD simulation. In this work, we apply the method to a set of four kinases with diverse binding pockets, and their corresponding inhibitors (42 in total), chosen to showcase the general applicability of RE-EDS in prospective drug design campaigns. We show that for the targets studied, RE-EDS is able to model up to 13 ligands simultaneously with high sampling efficiency, leading to a substantial decrease in computational cost when compared to pairwise methods.
Permanent link
Publication status
published
Editor
Book title
Journal / series
Volume
Pages / Article No.
Publisher
Cambridge University Press
Event
Edition / version
Version 2
Methods
Software
Geographic location
Date collected
Date created
Subject
Free energy calculation; Kinase; Multistate methods
Organisational unit
09458 - Riniker, Sereina Z. / Riniker, Sereina Z.
Notes
Funding
212732 - Combining Molecular Dynamics and Machine Learning for Free Energy Calculation with Quantum-Mechanical Accuracy (SNF)
Related publications and datasets
Is previous version of: