13C NMR-based dereplication using MixONat software to decipher potent anti-cholinesterase compounds in Mesua lepidota bark
Document Type
Article
Publication Date
12-1-2023
Abstract
A bio-assay guided fractionation strategy based on cholinesterase assay combined with 13C NMR-based dereplication was used to identify active metabolites from the bark of Mesua lepidota. Eight compounds were identified with the aid of the 13C NMR-based dereplication software, MixONat, i.e., sitosterol (1), stigmasterol (2), alpha-amyrin (3), friedelin (6), 3 beta-friedelinol (7), betulinic acid (9), lepidotol A (10) and lepidotol B (11). Further bio-assay guided isolation of active compounds afforded one xanthone, pyranojacareubin (12) and six coumarins; lepidotol A (10), lepidotol B (11), lepidotol E (13), lepidotin A (14), and lepidotin B (15), including a new Mammea coumarin, lepidotin C (16). All the metabolites showed strong to moderate butyrylcholinesterase (BChE) inhibition. Lepidotin B (15) exhibited the most potent inhibition towards BChE with a mix-mode inhibition profile and a Ki value of 1.03 mu M. Molecular docking and molecular dynamics simulations have revealed that lepidotin B (15) forms stable interactions with key residues within five critical regions of BChE. These regions encompass residues Asp70 and Tyr332, the acyl hydrophobic pocket marked by Leu286, the catalytic triad represented by Ser198 and His438, the oxyanion hole (OH) constituted by Gly116 and Gly117, and the choline binding site featuring Trp82. To gauge the binding strength of lepidotin B (15) and to pinpoint pivotal residues at the binding interface, free energy calculations were conducted using the Molecular Mechanics Generalized Born Surface Area (MM-GBSA) approach. This analysis not only predicted a favourable binding affinity for lepidotin B (15) but also facilitated the identification of significant residues crucial for the binding interaction.
Keywords
Dereplication, Mesua, MixONat, Coumarin, Cholinesterase
Divisions
chemistry,CHEMISTRY,cenar
Funders
French Ministry of Foreign Affairs, Malaysian Ministry of Higher Education, French Embassy in Malaysia,IFM-NatProLab,International French Malaysia Natural Product Laboratory,Universiti Malaya [Grant no. IF019-2020, RK011-2020],Centre National de la Recherche Scientifique
Publication Title
Bioorganic Chemistry
Volume
141
Publisher
Elsevier
Publisher Location
525 B ST, STE 1900, SAN DIEGO, CA 92101-4495 USA