Computer-aided identification of Mycobacterium tuberculosis resuscitation-promoting factor B (RpfB) inhibitors from Gymnema sylvestre natural products

Mohibullah Shah; Fatiha Khan; Iqra Ahmad; Cun-Liang Deng; Asia Perveen; Anwar Iqbal; Umar Nishan; Aqal Zaman; Riaz Ullah; Essam A Ali; Ke Chen

doi:10.3389/fphar.2023.1325227

Computer-aided identification of Mycobacterium tuberculosis resuscitation-promoting factor B (RpfB) inhibitors from Gymnema sylvestre natural products

Front Pharmacol. 2023 Nov 29:14:1325227. doi: 10.3389/fphar.2023.1325227. eCollection 2023.

Authors

Mohibullah Shah^#¹, Fatiha Khan^#¹, Iqra Ahmad¹, Cun-Liang Deng², Asia Perveen¹, Anwar Iqbal³, Umar Nishan⁴, Aqal Zaman⁵, Riaz Ullah⁶, Essam A Ali⁷, Ke Chen²

Affiliations

¹ Department of Biochemistry, Bahauddin Zakariya University, Multan, Pakistan.
² Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, China.
³ Department of Chemical Sciences, University of Lakki Marwat, Lakki Marwat, Pakistan.
⁴ Department of Chemistry, Kohat University of Science and Technology, Kohat, Pakistan.
⁵ Department of Microbiology and Molecular Genetics, Bahauddin Zakariya University, Multan, Pakistan.
⁶ Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
⁷ Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.

^# Contributed equally.

Abstract

Tuberculosis (TB), an infectious disease caused by multi-drug resistant Mycobacterium tuberculosis (Mtb), has been a global health concern. Mtb affects over a third of the world's population, causing two million deaths annually due to its dormancy and propensity to spread infection during this period. Resuscitation-promoting factor B (RpfB) plays a pivotal role in the growth of Mtb during dormant periods, making it a critical target for eliminating Mtb and curing TB. Gymnema sylvestre is a famous medicinal plant with several medicinal properties, including antimicrobial activity; however, the therapeutic potential of the various reported metabolites of this plant against Mtb has not yet been explored. The aim of this study was to explore the reported natural products of G. sylvestre against the RpfB of the Mtb. A total of 131 reported secondary metabolites of this plant were collected and virtually screened against the RpfB. We particularly targeted the Glu292 residue of RpfB as it is crucial for the catalysis of this protein. From our in-house library, 114 compounds showed a binding affinity higher than the standard drug. The binding stability of the top three lead compounds was further confirmed through MD simulation analysis. Drug likeness analyses indicated that the ten hits had zero violations of the Lipinski rule of five. In addition, analyses of pharmacokinetics, toxicity, and target prediction revealed that the top compounds are devoid of toxicity and do not affect human proteins. Additionally, they reflect multifaceted approach as anti-TB agents. Our selected hits not only exhibit molecular properties favoring physiological compatibility but also exhibit properties enhancing their potential efficacy as therapeutic candidates. The compounds investigated here are worthy of experimental validation for the discovery of novel treatments against TB. Further, this study also provides a promising avenue for research on the pharmacological potential of G. sylvestre.

Keywords: Gymnema sylvestre; RpfB; dormancy; in-silico; multi-drug resistance; tuberculosis.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This research work was supported by the Doctoral Research Fund awarded to KC. The research work was also supported by the researchers supporting Project number (RSP-2023R45) at King Saud University, Riyadh, Saudi Arabia.