Dataset Information

Binding profile of protein-ligand inhibitor complex and structure based design of new potent compounds via computer-aided virtual screening.

ABSTRACT:

Background

Mycobacterium tuberculosis protein target (DNA gyrase) is a type II topoisomerase target present in all bacteria. The enzyme comprises of two subunits A and B. DNA binding domain is located in the subunits A while the catalysis and cleavage of two DNA strands occur in the subunits A using ATP hydrolysis. This enzyme has been reported to emerge in extensively drug resistant tuberculosis. Therefore this research aimed to design new potent compounds against the target and establish the analysis of protein-ligand binding interaction between the target and novel quinoline analogues via the application of in silicovirtual screening to predict the inhibition binding affinities the analogues.

Result

The docking results revealed that compound ID 17 with efficient inhibition activity has a noticeable binding affinity of -18.8 kcal/mol. Hence compound 17 was designated as the reference template to designed novel fourteen compounds with higher binding affinities as a promising compounds.

Conclusion

Designed compound 17i, 17j and 17n with lead binding affinities among the designed compounds were observed with the most perceptible binding affinity which ranges from (-21.2 to -26.8) kcal/mol compared to low binding affinity (-5.8 kcal/mol) computed for ethambutol.

SUBMITTER: Shallangwa GA

PROVIDER: S-EPMC8258700 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Botulinum neurotoxin serotype A (BoNTA) causes a life-threatening neuroparalytic disease known as botulism. Current treatment for post exposure of BoNTA uses antibodies that are effective in neutralizing the extracellular toxin to prevent further intoxication but generally cannot rescue already intoxicated neurons. Effective small-molecule inhibitors of BoNTA endopeptidase (BoNTAe) are desirable because such inhibitors potentially can neutralize the intracellular BoNTA and offer complementary treatment for botulism. Previously we reported a serotype-selective, small-molecule BoNTAe inhibitor with a K(i) (app) value of 3.8+/-0.8 microM. This inhibitor was developed by lead identification using virtual screening followed by computer-aided optimization of a lead with an IC(50) value of 100 microM. However, it was difficult to further improve the lead from micromolar to even high nanomolar potency due to the unusually large enzyme-substrate interface of BoNTAe. The enzyme-substrate interface area of 4,840 A(2) for BoNTAe is about four times larger than the typical protein-protein interface area of 750-1,500 A(2). Inhibitors must carry several functional groups to block the unusually large interface of BoNTAe, and syntheses of such inhibitors are therefore time-consuming and expensive. Herein we report the development of a serotype-selective, small-molecule, and competitive inhibitor of BoNTAe with a K(i) value of 760+/-170 nM using synthesis-based computer-aided molecular design (SBCAMD). This new approach accounts the practicality and efficiency of inhibitor synthesis in addition to binding affinity and selectivity. We also report a three-dimensional model of BoNTAe in complex with the new inhibitor and the dynamics of the complex predicted by multiple molecular dynamics simulations, and discuss further structural optimization to achieve better in vivo efficacy in neutralizing BoNTA than those of our early micromolar leads. This work provides new insight into structural modification of known small-molecule BoNTAe inhibitors. It also demonstrates that SBCAMD is capable of improving potency of an inhibitor lead by nearly one order of magnitude, even for BoNTAe as one of the most challenging protein targets. The results are insightful for developing effective small-molecule inhibitors of protein targets with large active sites.