In Silico Drug Repurposing Approach: Investigation of Mycobacterium tuberculosis FadD32 Targeted by FDA-Approved Drugs

Abstract

Background: Despite the enormous efforts made towards combating tuberculosis (TB), the disease remains a major global threat. Hence, new drugs with novel mechanisms against TB are urgently needed. Fatty acid degradation protein D32 (FadD32) has been identified as a promising drug target against TB, the protein is required for the biosynthesis of mycolic acids, hence, essential for the growth and multiplication of the mycobacterium. However, the FadD32 mechanism upon the binding of FDA-approved drugs is not well established. Herein, we applied virtual screening (VS), molecular docking, and molecular dynamic (MD) simulation to identify potential FDA-approved drugs against FadD32. Methodology/Results: VS technique was found promising to identify four FDA-approved drugs (accolate, sorafenib, mefloquine, and loperamide) with higher molecular docking scores, ranging from −8.0 to −10.0 kcal/mol. Post-MD analysis showed that the accolate hit displayed the highest total binding energy of −45.13 kcal/mol. Results also showed that the accolate hit formed more interactions with FadD32 active site residues and all active site residues displayed an increase in total binding contribution. RMSD, RMSF, Rg, and DCCM analysis further supported that the presence of accolate exhibited more structural stability, lower bimolecular flexibility, and more compactness into the FadD32 protein. Conclusions: Our study revealed accolate as the best potential drug against FadD32, hence a prospective anti-TB drug in TB therapy. In addition, we believe that the approach presented in the current study will serve as a cornerstone to identifying new potential inhibitors against a wide range of biological targets.

Exploring the Therapeutic Potential of Petiveria alliacea L. Phytochemicals: A Computational Study on Inhibiting SARS-CoV-2’s Main Protease (Mpro)

“…directions [78]. Thus, the region of 0.5 to 1.0 represents a strong correlation, whereas the region of −0.5 to −1.0 shows a strong reverse correlation [79].…”

Potential Repurposed Drug Candidates for Tuberculosis Treatment: Progress and Update of Drugs Identified in Over a Decade

“…SRB in combination of Rifampicin and Isoniazid resulted in increased killing of the M.tb by inhibiting ABCG2 efflux pumps of the bone-marrow mesenchymal stem cells (BM-MSCs) . A recent study reported fatty acid degradation protein D32 (FadD32) as another target of SRB …”

“…97 A recent study reported fatty acid degradation protein D32 (FadD32) as another target of SRB. 104 Another anticancer drug Bortezomib is a proteasome inhibitor that is used for treating multiple myeloma. 105 This drug inhibits the growth of tumor cell by affecting (NFkB) signaling pathway of activated B cells and by inhibiting interleukin (IL)-6 signaling.…”

“… 97 A recent study reported fatty acid degradation protein D32 (FadD32) as another target of SRB. 104 …”

Anki̇lozan Spondi̇li̇t Tedavi̇si̇nde İlaç Yeni̇den Yerleşti̇rme Yaklaşimi

“…Drug repositioning, in other words, drug repurposing, is a set of methods that enable us to investigate the use of drug molecules that have been clinically approved or whose phase studies are in progress, outside of their medical indications. It provides a great advantage in terms of both time and cost compared to the detection of a completely new drug molecule, since it works with molecules that have been clinically and preclinically determined to be safe [25][26][27].…”