Accuracy and precision of binding free energy prediction for a tacrine related lead inhibitor of acetylcholinesterase with an arsenal of supercomputerized molecular modelling methods: a comparative study

Abstract

Nowadays, advanced computational chemistry methods offer various strategies for revealing prospective hit structures in drug development essentially through accurate binding free energy predictions. After the era of molecular docking and quantitative structure-activity relationships, much interest has been lately oriented to perturbed molecular dynamic approaches like replica exchange with solute tempering and free energy perturbation (REST/FEP) and the potential of the mean force with adaptive biasing and accelerated weight histograms (PMF/AWH). Both of these receptor-based techniques can exploit exascale CPU&GPU supercomputers to achieve high throughput performance. In this fundamental study, we have compared the predictive power of a panel of supercomputerized molecular modelling methods to distinguish the major binding modes and the corresponding binding free energies of a promising tacrine related potential antialzheimerics in human acetylcholinesterase. The binding free energies were estimated using flexible molecular docking, molecular mechanics/generalized Born surface area/Poisson-Boltzmann surface area (MM/GBSA/PBSA), transmutation REST/FEP with 12 x 5 ns/λ windows, annihilation FEP with 20 x 5 ns/λ steps, PMF with weight histogram analysis method (WHAM) and 40 x 5 ns samples, and PMF/AWH with 10 x 100 ns replicas. Confrontation of the classical approaches such as canonical molecular dynamics and molecular docking with alchemical calculations and steered molecular dynamics enabled us to show how large errors in ΔG predictions can be expected if these in silico methods are employed in the elucidation of a common case of enzyme inhibition.

Communicated by Ramaswamy H. Sarma

Keywords:

• Molecular modelling
• tacrine
• acetylcholinesterase
• binding free energy
• Alzheimer’s disease

Disclosure statement

No potential conflict of interest was reported by the authors.

Author contributions

R. D. performed the calculations and wrote the article.

Additional information

Funding

This work was supported by the Ministry of Education, Youth and Sports of the Czech Republic [project ERDF no. CZ.02.1.01/0.0/0.0/18_069/0010054] and by MH CZ - DRO [University Hospital Hradec Kralove, no. 00179906]. Access to computing and storage facilities owned by parties and projects contributing to the National Grid Infrastructure MetaCentrum provided under the programme ‘Projects of Large Research, Development, and Innovations Infrastructures’ (CESNET LM2015042), is greatly appreciated. This work was also supported by the Ministry of Education, Youth and Sports from the Large Infrastructures for Research, Experimental Development and Innovations project „e-Infrastructure CZ – LM2018140“. MD, MM/PBSA, FEP and PMF calculations were performed on the supercomputer Sofia of the University of Hradec Kralove. Flexible molecular docking in AutoDock 4.2.6 and AutoDock Vina 1.1.2 was performed in MetaCentrum. IFD and MM/GBSA calculations were performed on the supercomputer Salomon of IT4 Innovations.