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Research Articles

Design of dipicolinic acid derivatives as New Delhi metallo-β-lactamase-1 inhibitors using a combined computational approach

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Pages 3384-3395 | Received 30 Apr 2019, Accepted 12 Aug 2019, Published online: 24 Sep 2019
 

Abstract

New Delhi metallo-β-lactamase (NDM-1) is the most recent addition to the class of metallo-β-lactamases (MBLs). This enzyme leads to antibiotic resistance in clinical treatments owing to its exertion of hydrolysis activity in almost all clinically available β-lactam antibiotics. Consequently, inhibitors targeting NDM-1 have attracted considerable research attention. However, progress has been slow regarding the study of the quantitative structure-activity relationship (QSAR) of NDM-1 inhibitors. In this study, a three-dimensional QSAR (3 D-QSAR) for NDM-1 inhibitors was established using Topomer CoMFA. The multiple correlation coefficients of the fitting model, leave-one-out cross validation, and external validation were found to be 0.761, 0.976, and 0.972, respectively. Topomer Search was used to design 16 new molecules that inhibit NDM-1 using R-group search from ZINC databases, 10 of which had comparatively high activities against NDM-1. The results indicate that Topomer CoMFA and Topomer Search can be used to design new NDM-1 inhibitors and guide the design of new NDM-1 drugs with good predictive capability. Furthermore, from molecular modeling and binding free-energy calculation, it was found that the newly designed molecules can bind to the catalytic region of NDM-1. Additionally, the newly designed inhibitors formed strong interactions with Ile35, Met67, Phe70, Trp93, His122, His189, Cys208, and His250 around the Zn2+-centered active region of NDM-1. These findings will facilitate the development of more effective NDM-1 inhibitors for use as potential antibacterial agents.

Communicated by Ramaswamy H. Sarma

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The authors acknowledge the financial support from the National Nature Science Foundation of China [Grant no. 31572566 to X. D. N].

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