ABSTRACT
Aim of this study was to synthesize new inhibitors on the basis of active site of aspartic protease enzyme and to evaluate their intended biological activity. A3D model of an enzyme was generated via homology modeling and series of novel amide ligands were synthesized by using a short high yield process, subsequently, analyzed in-silico and in-vitro anti-leishmanial activities. Characterization and identification was accomplished via NMR (H1& C13), infrared and mass spectroscopic techniques. Among all compound (4) was found to show significant activity (IC50 58±0.01) against Leishmania major (L. major) species. Furthermore, docking studies confirmed the inhibition of a targeted enzyme that supported the interaction of potent compound (4) with key residues (aspartic protease) via hydrogen bonds. Present study conferred about novel compound (4) as a promising compound to antagonize L. major activities in future.
Subject(s)
Amides/chemical synthesis , Antiprotozoal Agents/chemical synthesis , Leishmania/drug effects , Molecular Docking Simulation/methods , Amides/metabolism , Amides/pharmacology , Antiprotozoal Agents/metabolism , Antiprotozoal Agents/pharmacology , Leishmania/metabolism , Ligands , Molecular Structure , Protein Structure, Secondary , Structure-Activity RelationshipABSTRACT
Medicinal plants of Pakistan are known for their curative properties against snake bite as rural people have been using natural herbs for such injuries for hundreds to thousands of years. People of rural areas of Pakistan are prone to snakebite, and on the whole death due to snakebite has been increasing worldwide. The objective of this study was to test the neutralizing potential of 17 Pakistani medicinal plant extracts against phospholipase A2 activity in Echis carinatus venom. Plant material was extracted by simple maceration and fractionation of active plant extracts. Venom was collected by manual massage of the venom glands. The PLA2 enzymatic assay was performed to map out the venomous activity of Echis carinatus envenomation. Snake venom released fatty acids at different concentrations (0.1-5 mg/ml) of venom in a dose-dependent manner. Reduction of pH by 01 correlated with 133 µmol of fatty acids released at 5mg/ml of venom. All plants extract inhibited PLA2 activity, however, Curcuma longa, Citrullus colocynthis and Rubia cordifolia inhibited maximum of PLA2 activity (â78%) comparable to the standard antidote (p>0.5). Medicinal plants possess secondary metabolites and many active compounds that may have neutralizing or inhibiting properties against the PLA2 activity of Echis venom. Further studies such as compound analysis could provide an alternative against snakebites injuries resulting from Echis carinatus venom.
