Conformational Ensembles from Experimental Data and Computer Simulations

Conformational Ensembles from Experimental Data and Computer Simulations

Poster Abstracts

46-POS Board 6 MM-GBSA, Gaussian and Electronic Circular Dichroism (ECD) Determination of Absolute Configuration and Binding Efficacy of Benzimidazole-Based Fabi Inhibitors Michael E. Johnson 1,2 , Jinhong Ren 1 , Tina L. Mistry 1 , Pin-Chih Su 1 , Shahila Mehboob 2 . 1 University of Illinois at Chicago, Chicago, IL, USA, 2 Novalex Therapeutics, Inc., Chicago, IL, USA. We have reported benzimidazole-based compounds to be potent inhibitors of FabI for both F. tularensis and S. aureus (FtFabI, SaFabI), making them promising antimicrobial hits. Optically active enantiomers exhibit markedly differing affinities toward FtFabI. The IC50 of benzimidazole 6-(-) is ~100x lower than the (+)-enantiomer, with similar results for enantiomers of 7. Determining the absolute configuration (AC) for these optical compounds and elucidating their binding modes is important for further design. Electronic Circular Dichroism (ECD) calculated by quantum methods has become important in AC determination of optical compounds. The AC of 6-(-)/(+) and 7-(-)/(+) were determined by comparing experimental spectra and theoretical DFT simulations of ECD at the B3LYP/6-311+G(2d, p) level using Gaussian09. Comparison of experimental and calculated ECD spectra indicates that the S configuration corresponds to the (-)-rotation for both compounds 6 and 7, while the R configuration corresponds to the (+)-rotation. Further, MD simulations and MM-GBSA binding free energy calculations for these two pairs of enantiomers with FtFabI show much tighter binding MM-GBSA free energies for 6- S and 7- S than for their enantiomers, 6- R and 7- R , consistent with experimental observations that the (-)-enantiomers were more active. The results are consistent with the ECD determination of the S configuration corresponding to (-) and the R configuration corresponding to (+). Finally, fifteen benzimidazoles, including these optically active compounds were subjected to systematic MD simulations and MM-GBSA predictions for SaFabI binding. The predicted absolute configuration is further confirmed by the resulting coefficient of R 2 =0.80 between experimental and MM-GBSA predicted binding free energies. Thus, our computational studies allow us to assign (+)-( R )- and (-)-( S )-compounds 6 and 7, and to further evaluate structural changes to improve efficacy. 6 = 1-(1-(3,4-dichlorophenyl)ethyl)-1,5,6,7-tetrahydroindeno[5,6-d]imidazole 7 = 1-(1-(3,4-dichlorophenyl)ethyl)-5,6,7,8-tetrahydro-1H-naphtho[2,3-d]imidazole

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