Optimizing Bedaquiline for cardiotoxicity by structure based virtual screening, DFT analysis and molecular dynamic simulation studies to identify selective MDR-TB inhibitors

Iqrar Ahmad; Harsha Jadhav; Yashodeep Shinde; Vilas Jagtap; Rukaiyya Girase; Harun Patel

doi:10.1007/s40203-021-00086-x

Optimizing Bedaquiline for cardiotoxicity by structure based virtual screening, DFT analysis and molecular dynamic simulation studies to identify selective MDR-TB inhibitors

In Silico Pharmacol. 2021 Mar 23;9(1):23. doi: 10.1007/s40203-021-00086-x. eCollection 2021.

Authors

Iqrar Ahmad¹, Harsha Jadhav¹, Yashodeep Shinde¹, Vilas Jagtap¹, Rukaiyya Girase¹, Harun Patel¹

Affiliation

¹ Division of Computer Aided Drug Design, Department of Pharmaceutical Chemistry, R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur, Dhule, 425405 Maharashtra India.

Abstract

Since the last 4 decades, Bedaquiline has been the first drug discovered as a new kind of anti-tubercular agent and received FDA approval in December 2012 to treat pulmonary multi-drug resistance tuberculosis (MDR-TB). It demonstrates excellent efficacy against MDR-TB by effectively inhibiting mycobacterial ATP synthase. In addition to these apparent assets of Bedaquiline, potential disadvantages of Bedaquiline include inhibition of the hERG (human Ether-à-go-related gene; KCNH2), potassium channel (concurrent risk of cardiac toxicity), and risk of phospholipidosis due to its more lipophilic nature. To assist the effective treatment of MDR-TB, highly active Bedaquiline analogs that display a better safety profile are urgently needed. A structure-based virtual screening approach was used to address the toxicity problems associated with Bedaquiline. Among the virtually screened compound, CID 15947587 had significant docking affinity (- 5.636 kcal/mol) and highest binding free energy (ΔG bind - 85.2703 kcal/mol) towards the Mycobacterial ATP synthase enzyme with insignificant cardiotoxicity and lipophilicity. During MD simulation studies (50 ns), the molecule optimizes its conformation to fit better the active receptor site justifying the binding affinity. The obtained results showed that CID15947587 could be a useful template for further optimizing the MDR-TB inhibitor.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-021-00086-x.

Keywords: Bedaquiline; Docking; HERG; MD simulation; MMGBSA.