Discovery of new targeting agents against GAPDH receptor for antituberculosis drug delivery

Abstract

Abstract Objectives Tuberculosis (TB) remains a public health concern due to the emergence and evolution of multidrug-resistant strains. To overcome this issue, reinforcing the effectiveness of first line antituberculosis agents using targeted drug delivery approach is an option. Glyceraldehyde-3-Phosphate Dehydrogenase (GADPH), a common virulence factor found in the pathogenic microorganisms has recently been discovered on the cell-surface of Mycobacterium tuberculosis, allowing it to be used as a drug target for TB. This study aims to discover active small molecule(s) that target GAPDH and eventually enhance the delivery of antituberculosis drugs. Methods Ten ligands with reported in vitro and/or in vivo activities against GAPDH were evaluated for their binding interactions through molecular docking studies using AutoDock 4.2 program. The ligand with the best binding energy was then modified to produce 10 derivatives, which were redocked against GAPDH using previous protocols. BIOVIA Discovery Studio Visualizer 2019 was used to explore the ligand-receptor interactions between the derivatives and GAPDH. Results Among the 10 ligands, curcumin, koningic acid and folic acid showed the best binding energies. Further analysis on the docking of two folic acid derivatives, F7 (γ-{[tert-butyl-N-(6-aminohexyl)]carbamate}folic acid) and F8 (folic acid N-hydroxysuccinimide ester) showed that the addition of a bulky substituent at the carboxyl group of the glutamic acid subcomponent resulted in improved binding energy. Conclusions Folic acid and the two derivatives F7 and F8 have huge potentials to be developed as targeting agents against the GAPDH receptor. Further study is currently on-going to evaluate the effectiveness of these molecules in vitro.