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

Noh MAA, Fazalul Rahiman SS, A Wahab H, Mohd Gazzali A

J Basic Clin Physiol Pharmacol, 2021 Jun 25;32(4):715-722.
PMID: 34214294 DOI: 10.1515/jbcpp-2020-0435

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.
Fulltext Antituberculosis Targeted Drug Delivery as a Potential Future Treatment Approach

Mazlan MKN, Mohd Tazizi MHD, Ahmad R, Noh MAA, Bakhtiar A, Wahab HA, et al.

Antibiotics (Basel), 2021 Jul 25;10(8).
PMID: 34438958 DOI: 10.3390/antibiotics10080908

Mycobacterium tuberculosis (Mtb) is the microorganism that causes tuberculosis. This infectious disease has been around for centuries, with the earliest record of Mtb around three million years ago. The discovery of the antituberculosis agents in the 20th century has managed to improve the recovery rate and reduce the death rate tremendously. However, the conventional antituberculosis therapy is complicated by the development of resistant strains and adverse drug reactions experienced by the patients. Research has been conducted continuously to discover new, safe, and effective antituberculosis drugs. In the last 50 years, only two molecules were approved despite laborious work and costly research. The repurposing of drugs is also being done with few drugs; antibiotics, particularly, were found to have antituberculosis activity. Besides the discovery work, enhancing the delivery of currently available antituberculosis drugs is also being researched. Targeted drug delivery may be a potentially useful approach to be developed into clinically accepted treatment modalities. Active targeting utilizes a specifically designed targeting agent to deliver a chemically conjugated drug(s) towards Mtb. Passive targeting is very widely explored, with the development of multiple types of nanoparticles from organic and inorganic materials. The nanoparticles will be engulfed by macrophages and this will eliminate the Mtb that is present in the macrophages, or the encapsulated drug may be released at the sites of infections that may be in the form of intra- and extrapulmonary tuberculosis. This article provided an overview on the history of tuberculosis and the currently available treatment options, followed by discussions on the discovery of new antituberculosis drugs and active and passive targeting approaches against Mycobacterium tuberculosis.

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