ao9b04233_si_002.xlsx (40.56 kB)
Fast, Accurate, and Reliable Protocols for Routine Calculations of Protein–Ligand Binding Affinities in Drug Design Projects Using AMBER GPU-TI with ff14SB/GAFF
dataset
posted on 2020-02-25, 17:03 authored by Xibing He, Shuhan Liu, Tai-Sung Lee, Beihong Ji, Viet H. Man, Darrin M. York, Junmei WangAccurate
prediction of the absolute or relative protein–ligand
binding affinity is one of the major tasks in computer-aided drug
design projects, especially in the stage of lead optimization. In
principle, the alchemical free energy (AFE) methods such as thermodynamic
integration (TI) or free-energy perturbation (FEP) can fulfill this
task, but in practice, a lot of hurdles prevent them from being routinely
applied in daily drug design projects, such as the demanding computing
resources, slow computing processes, unavailable or inaccurate force
field parameters, and difficult and unfriendly setting up and post-analysis
procedures. In this study, we have exploited practical protocols of
applying the CPU (central processing unit)-TI and newly developed
GPU (graphic processing unit)-TI modules and other tools in the AMBER
software package, combined with ff14SB/GAFF1.8 force fields, to conduct
efficient and accurate AFE calculations on protein–ligand binding
free energies. We have tested 134 protein–ligand complexes
in total for four target proteins (BACE, CDK2, MCL1, and PTP1B) and
obtained overall comparable performance with the commercial Schrodinger
FEP+ program (Wang J. Am. Chem. Soc. 2015, 137, 2695−2703). The achieved accuracy fits within the requirements
for computations to generate effective guidance for experimental work
in drug lead optimization, and the needed wall time is short enough
for practical application. Our verified protocol provides a practical
solution for routine AFE calculations in real drug design projects.