Repositioning FDA-approved drugs to identify potential mycobacterial FadD23 inhibitors.

Abstract

Tuberculosis (TB) is a respiratory disease caused by Mycobacterium tuberculosis (M. tuberculosis). The high transmission and mortality rates show that the medical and scientific community need new strategies to combat the TB burden. One strategy would be repurposing drugs which have already been Food and Drug Administration (FDA)-approved to aid in discovery of potential inhibitors against novel TB drug targets. This project aimed to identify a potential inhibitor of FadD23 through in silico screening of FDA-approved drugs against the FadD23 protein structure. Ligand structures were retrieved from the ZINC database and docked into FadD23 using AutoDock Vina. Simeprevir had the highest docking score (-10.5 kcal/mol), and was further subjected to 600 ns molecular dynamics (MD) simulations using Amber 18, with Phosphoaminophosphonic acid-adenylate (ANP) used as a control ligand. Post-MD analysis namely root mean square deviation (RMSD), root mean square fluctuations (RMSF), hydrogen bond (Hbond), radius of gyration (Rg), dynamic secondary structure elements (SSE), and distances were calculated using a CPPTRAJ module. Binding affinities of ligands were calculated using MM/GBSA module. The results of RMSD showed that Simeprevir (2.23 Å) was stable during simulations, where its bulky hydrophobic conformation governed complex stability. This was also supported by the compact conformation of FadD23 structure induced by Simeprevir. Simeprevir also had a higher binding affinity (-33.87 kcal/mol) compared to ANP (-17.95 kcal/mol), where its binding affinity was driven by electrostatic and van der Waals forces. Energy contributions from Thr177, Thr176, Arg555, Ala179, Lys553, and Arg460 notably influenced Simeprevir’s binding affinity. RMSF suggested that Simeprevir made contact with both the N- and C-terminal domains of FadD23, where it suppressed residue displacement in the N-terminal domain and induced notable residue displacement in the C-terminal domain. SSE analysis showed that Simeprevir potentially arrests FadD23 function by altering native secondary structure elements. At present, there’s no reported drug that has been approved by the FDA against FadD23, nor existence of records showing clinical studies of potential inhibitors of FadD23. Compound 5’-O-[N-(11-phenoxyundecanoyl) sulfamoyl] adenosine (Phu-Ams) was reported to be a general inhibitor of FadD enzymes; however, its interaction with FadD23 did not involve the C-terminal domain. This differs from Simeprevir, where it was noted to form interactions with residues in the C-terminal domain, a domain that is responsible for substrate catalysis. The analysis based on molecular docking, MD simulations and subsequent post-MD trajectory analysis suggest that Simeprevir may be able to serve as a potential inhibitor of FadD23, thus potentially interferes with SL-1 production in M. tuberculosis.