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

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.

Fig. 1

Virtual screening protocol

Fig. 2

Data obtained in the validation of the molecular docking protocol, the impeccably overlapped conformation of the docked ligand Bedaquiline with respect to its crystallized conformation obtained from the bioactive complex structure; cyan ligand: native ligand; sky blue ligand: docked pose

Fig. 3

Binding-interaction analysis of a Bedaquiline; b CID15947587; c CID49767237 with Mycobacterial ATP synthase (PDB: 41VF) domain

Fig. 4

The correlation plot between MM-GBSA values (primary y-axis) and docking score (secondary y-axis) for the control molecule (Bedaquiline) and 9 finalized potential hits

Fig. 5

Time-dependent protein–ligand RMSD plot (Angstrom) of the CID15947587 with Mycobacterial ATP synthase enzyme binding pocket

Fig. 6

Time-dependent protein RMSF plot (Angstrom) of the CID 15947587 with mycobacterial ATP synthase enzyme binding pocket

Fig. 7

Simulation interactions diagram, 2D binding interaction of CID 15947587 with mycobacterial ATP synthase enzyme binding pocket along with bar diagram

Fig. 8

Protein–ligand contacts showing good contacts (darker shades) with the amino acid residues over 50 ns time period of simulation of the CID 15947587 with mycobacterial ATP synthase enzyme binding pocket

Fig. 9

Ligand properties during 50 ns simulations for CID15947587: a ligand RMSD, root mean square deviation, b radius of gyration (rGyr), c molecular surface area (MolSA), d solvent accessible surface area (SASA), and e polar surface area (PSA)

Fig. 10

Plots of the HOMO, LUMO and HLG of CID 15947587 (a) and Bedaquiline (b)