title: Evaluating thermodynamic integration performance of the new amber molecular dynamics package and assess potential halogen bonds of enoyl-ACP reductase (FabI) benzimidazole inhibitors.
abstract: Thermodynamic integration (TI) can provide accurate binding free energy insights in a lead optimization program, but its high computational expense has limited its usage. In the effort of developing an efficient and accurate TI protocol for FabI inhibitors lead optimization program, we carefully compared TI with different Amber molecular dynamics (MD) engines (sander and pmemd), MD simulation lengths, the number of intermediate states and transformation steps, and the Lennard-Jones and Coulomb Softcore potentials parameters in the one-step TI, using eleven benzimidazole inhibitors in complex with Francisella tularensis enoyl acyl reductase (FtFabI). To our knowledge, this is the first study to extensively test the new AMBER MD engine, pmemd, on TI and compare the parameters of the Softcore potentials in the one-step TI in a protein-ligand binding system. The best performing model, the one-step pmemd TI, using 6 intermediate states and 1 ns MD simulations, provides better agreement with experimental results (RMSD = 0.52 kcal/mol) than the best performing implicit solvent method, QM/MM-GBSA from our previous study (RMSD = 3.00 kcal/mol), while maintaining similar efficiency. Briefly, we show the optimized TI protocol to be highly accurate and affordable for the FtFabI system. This approach can be implemented in a larger scale benzimidazole scaffold lead optimization against FtFabI. Lastly, the TI results here also provide structure-activity relationship insights, and suggest the parahalogen in benzimidazole compounds might form a weak halogen bond with FabI, which is a well-known halogen bond favoring enzyme.
authors.affiliation: Center for Pharmaceutical Biotechnology, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, 60607.
authors.forename: Pin-Chih
authors.initials: PC
authors.lastname: Su
authors.affiliation: Center for Pharmaceutical Biotechnology, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, 60607.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Johnson
mesh_terms: D001562:Benzimidazoles / Q000737:chemistry* / Q000494:pharmacology*; D004746:Enoyl-CoA Hydratase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005604:Francisella tularensis / Q000201:enzymology; D006219:Halogens / Q000737:chemistry*; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D013816:Thermodynamics
chemical_list: D001562:Benzimidazoles; D004791:Enzyme Inhibitors; D006219:Halogens; D004746:Enoyl-CoA Hydratase
keywords: benzimidazole-based inhibitors; enoyl acyl reductase (FabI), explicit solvent models; free energy calculation; halogen bond; implicit solvent models; thermodynamic integration