Visceral leishmaniasis is an important public health threat in parts of India. It is caused by a protozoan parasite, Currently available drugs manifest severe side effects. Hence, there is a need to identify new drug targets and drugs. Aminoacyl-tRNA synthetases, required for protein synthesis, are known drug targets for bacterial and fungal pathogens. The aim of the present study was to obtain essentiality data for leucyl-tRNA synthetase (LRS) by gene replacement. Gene replacement studies indicate that this enzyme plays an essential role in the viability of this pathogenic organism and appears to be indispensable for its survival The heterozygous mutant parasites demonstrated a growth deficit and reduced infectivity in mouse macrophages compared to the wild-type cells. We also report that recombinant LRS displayed aminoacylation activity and that the protein localized to both the cytosol and the mitochondrion. A broad-spectrum antifungal, 5-fluoro-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (AN2690), was found to inhibit parasite growth in both the promastigote and amastigote stages as well as in BALB/c mice. This compound exhibited low toxicity to mammalian cells. AN2690 was effective in inhibiting the aminoacylation activity of the recombinant LRS. We provide preliminary chemical validation ofLRS as a drug target by showing that AN2690 is an inhibitor both of LRS and of cell growth.
Objective: Alzheimer's disease (AD) is one of the most prevalent neurological ailments, affecting around 50 million individuals globally. The condition is characterized by nerve cell damage due to the formation of amyloid-beta plaques and neurofibrillary tangles. Only a few US Food and Drug Administration (FDA)-approved medications are available in the market which are devoid of side effects, thus, making it imperative to investigate new alternatives for countering this disease. According to a recent study, microtubule affinity regulation kinase 4 (MARK4) is attributed as one of the most promising drug targets for AD, thus, being selected for this study. Compounds from Ganoderma lucidum (Reishi mushroom) extracts were selected to be used as ligands for this study.
Methods:In this study, the five most potent compounds from Ganoderma lucidum were selected and their absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis was performed, followed by molecular docking, and molecular dynamics simulation of each compound with MARK4 and supported by molecular mechanics generalized born surface area (MMGBSA) binding free energy calculations.
Results:The promising compounds were selected based on their ADMET profile and interactions with the active site residues of MARK4. Based on docking scores of −9.1 and −10.3 kcal/ mol, respectively, stability assessment by molecular dynamics simulation, and MMGBSA calculations, ganoderic acid A and ganoderenic acid B were found to be the most promising compounds against MARK4 which will require further in vitro and in vivo validations.
Conclusion:Through this study, it is suggested that ganoderic acid A and ganoderenic acid B might be a class of promising compounds against AD, based on computational research, and can be further studied for preclinical and clinical studies.
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