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

, Tina L. Mistry

, Pin-Chih Su

, Shahila Mehboob

University of Illinois at Chicago, Chicago, IL, USA,

Novalex Therapeutics, Inc., Chicago, IL,

USA.

We have reported benzimidazole-based compounds to be potent inhibitors of FabI for both

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

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-

and 7-

than for their enantiomers, 6-

and 7-

consistent with experimental observations that the (-)-enantiomers were more active. The results

are consistent with the ECD determination of the

configuration corresponding to (-) and the

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

=0.80 between experimental and MM-GBSA predicted binding free energies.

Thus, our computational studies allow us to assign (+)-(

)- and (-)-(

)-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