In Silico Identification of Novel Derivatives of Rifampicin Targeting Ribonuclease VapC2 of M. tuberculosis H37Rv: Rifampicin Derivatives Target VapC2 of Mtb H37Rv

Satyamvada Maurya; Amita Jain; Md Tabish Rehman; Ali Hakamy; Farkad Bantun; Mohamed F AlAjmi; Vineeta Singh; Aafreen Zehra; Feroz Khan; Shafiul Haque; Bhartendu Nath Mishra

doi:10.3390/molecules28041652

In Silico Identification of Novel Derivatives of Rifampicin Targeting Ribonuclease VapC2 of M. tuberculosis H37Rv: Rifampicin Derivatives Target VapC2 of Mtb H37Rv

Molecules. 2023 Feb 8;28(4):1652. doi: 10.3390/molecules28041652.

Authors

Affiliations

¹ Department of Biotechnology, Institute of Engineering & Technology, Dr. A.P.J. Abdul Kalam Technical University, Lucknow 226021, India.
² Department of Microbiology, King George Medical University, Lucknow 226003, India.
³ Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
⁴ Respiratory Therapy Department, Faculty of Applied Medical Sciences, Jazan University, Jazan 45142, Saudi Arabia.
⁵ Department of Microbiology, Faculty of Medicine, Umm Al-Qura University, Makkah 21955, Saudi Arabia.
⁶ Technology Dissemination and Computational Biology Unit, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow 226015, India.
⁷ Research & Scientific Studies Unit, College of Nursing & Allied Health Sciences, Jazan University, Jazan 45142, Saudi Arabia.
⁸ Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Beirut 1102 2801, Lebanon.
⁹ Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman 13306, United Arab Emirates.

Abstract

The emergence of multi-drug-resistant Mycobacterium tuberculosis (Mtb) strains has rendered many of the currently available anti-TB drugs ineffective. Hence, there is a pressing need to discover new potential drug targets/candidates. In this study, attempts have been made to identify novel inhibitors of the ribonuclease VapC2 of Mtb H37Rv using various computational techniques. Ribonuclease VapC2 Mtb H37Rv's protein structure was retrieved from the PDB databank, 22 currently used anti-TB drugs were retrieved from the PubChem database, and protein-ligand interactions were analyzed by docking studies. Out of the 22 drugs, rifampicin (RIF), being a first-line drug, showed the best binding energy (-8.8 Kcal/mol) with Mtb H37Rv VapC2; hence, it was selected as a parent molecule for the design of its derivatives. Based on shape score and radial plot criteria, out of 500 derivatives designed through SPARK (Cresset^®, Royston, UK) program, the 10 best RIF derivatives were selected for further studies. All the selected derivatives followed the ADME criteria concerning drug-likeness. The docking of ribonuclease VapC2 with RIF derivatives revealed the best binding energy of -8.1 Kcal/mol with derivative 1 (i.e., RIF-155841). A quantitative structure-activity relationship study revealed that derivative 1's activity assists in the inhibition of ribonuclease VapC2. The stability of the VapC2-RIF155841 complex was evaluated using molecular dynamics simulations for 50 ns and the complex was found to be stable after 10 nsec. Further, a chemical synthesis scheme was designed for the newly identified RIF derivative (RIF-155841), which verified that its chemical synthesis is possible for future in vitro/in vivo experimental validation. Overall, this study evaluated the potential of the newly designed RIF derivatives with respect to the Mtb VapC2 protein, which is predicted to be involved in some indispensable processes of the related pathogen. Future experimental studies regarding RIF-155841, including the exploration of the remaining RIF derivatives, are warranted to verify our current findings.

Keywords: ADMET; Mycobacterium tuberculosis; molecular docking; radius of gyration; root mean square deviation; root mean square fluctuation; tuberculosis.

MeSH terms

Humans
Molecular Dynamics Simulation
Mycobacterium tuberculosis*
Ribonucleases / pharmacology
Rifampin / pharmacology
Sensitivity and Specificity
Tuberculosis*

Substances

Rifampin
Ribonucleases

Grants and funding

This research received no external funding.