Cholinergic Inhibition and Antioxidant Potential of Gongronema latifolium Benth Leaf in Neurodegeneration: Experimental and In Silico Study.

The use of Gongronema latifolium for the management of various forms of neurological disorders has generated a lot of interest in the need to further investigate its neurotherapeutic constituents. This work, therefore, focused on assessing the inhibitory potential of selected bioactive components derived from G. latifolium against key neurotherapeutic targets and oxidant species associated with neurodegeneration using in vitro analysis and biomolecular modelling. G. latifolium methanol extract (GLME), solvent partition, chromatographic fractions (A-F) of GLME and pregnane compounds (Iloneoside and marsectohexol) derived from fraction-B with the highest activity were investigated for in vitro acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and monoamine oxidase (MAO) inhibition in addition to their in vitro antioxidant activities. The interactions of iloneoside, marsectohexol, and reference drugs with human acetylcholinesterase, butyrylcholinesterase, and ß-secretase (BACE-1) were further assessed using molecular docking, binding free energy calculations, cluster analysis, and molecular dynamics simulations. The GLME and fractions inhibited the activities of both acetylcholinesterase and butyrylcholinesterase in a dose-dependent manner. Iloneoside and marsectohexol exhibited in vitro concentration-dependent inhibitory activities against acetylcholinesterase (IC50 = 19.28, 184.9 µM, respectively) and butyrylcholinesterase (IC50 = 30.75, 43.4 µM, respectively). These compounds also possess ferric ion-reducing, hydroxyl, and superoxide radical-scavenging activities. Iloneoside had the highest docking scores of -9.8, -9.9 -9.4 Kcal for AChE, BChE, and BACE1, respectively. The stability of the interaction of the bioactive compounds with the catalytic residues of the protein targets was preserved in a 100 ns molecular dynamics simulation. Iloneoside, a rare pregnane glycoside, was identified as a neurotherapeutic constituent of G. latifolium leaf. Further studies are suggested to investigate the neurotherapeutic potential in animal models.

Structure-based inhibition of acetylcholinesterase and butyrylcholinesterase with 2-Aryl-6-carboxamide benzoxazole derivatives: synthesis, enzymatic assay, and in silico studies.

An important research topic is the discovery of multifunctional compounds targeting different disease-causing components. This research aimed to design and synthesize a series of 2-aryl-6-carboxamide benzoxazole derivatives that inhibit cholinesterases on both the peripheral anionic and catalytic anionic sides. Compounds (7-48) were prepared from 4-amino-3-hydroxybenzoic acid in three steps. The Ellman test, molecular docking with Maestro, and molecular dynamics simulation studies with Desmond were done (Schrodinger, 12.8.117). Compound 36, the most potent compound among the 42 new compounds synthesized, had an inhibitory concentration of IC50 12.62 nM for AChE and IC50 25.45 nM for BChE (whereas donepezil was 69.3 nM and 63.0 nM, respectively). Additionally, compound 36 had docking values ​​of - 7.29 kcal/mol for AChE and - 6.71 kcal/mol for BChE (whereas donepezil was - 6.49 kcal/mol and - 5.057 kcal/mol, respectively). Furthermore, molecular dynamics simulations revealed that compound 36 is stable in the active gorges of both AChE (average RMSD: 1.98 Å) and BChE (average RMSD: 2.2 Å) (donepezil had average RMSD: 1.65 Å and 2.7 Å, respectively). The results show that compound 36 is a potent, selective, mixed-type dual inhibitor of both acetylcholinesterase and butyrylcholinesterase. It does this by binding to both the catalytically active and peripheral anionic sites of cholinesterases at the same time. These findings show that target compounds may be useful for establishing the structural basis for new anti-Alzheimer agents.

An in silico approach to investigate the theranostic potential of coumarin-derived self-immolative luminescent probes.

Till date the challenge exists in the treatments of cancer for various reasons. Most importantly, the available diagnostics are expensive with research gap for enhancing the cancer detection sensitivity. Herein, a series of coumarin-derived fluorescent theranostic probes are reported that can serve as potent anticancer agents as well as in the detection of cancer cells. The potential of these probes to efficiently block one of the well-known cancer drug targets NADPH quinone oxidoreductase-1 (NQO1) is evaluated through various pharmacokinetic methods including absorption, distribution, metabolism and excretion (ADME) properties evaluation, PASS (prediction of activity spectra for substance) algorithm along with molecular docking and dynamic simulations. Further the luminescent properties of these molecules were evaluated by investigating their electronic properties in the ground and excited states with the help of density functional theory methods. Results indicate that the proposed molecules can potentially block the NADPH (reduced form of nicotinamide adenine dinucleotide) binding site of NQO1, thereby inhibiting the activity of the enzyme to ultimately disrupt the metabolism of cancer cells.