Friedolanostanes from Garcinia benthamii Pierre: in silico Investigation of Anti-inflammatory Activity Targeting the NF-κB p50 Subunit

Abstract

An investigation of the chemical constituents present in the dichloromethane (DCM) extracts of rind, fruit, roots and leaves of Garcinia benthamii Pierre has led to an isolation of a new triterpene (24E)-23-acetoxy-3α- hydroxylanosta-9(11),16,24-trien-26-oic acid (1), squalene and triacylglycerols from the roots; methyl (24E)- 3α,9α,23-trihydroxy-17,14-friedolanosta-14,24-dien-26-oate (2), caryophyllene, squalene, a mixture of compound 1, (22Z,24E)-9α-hydroxy-3-oxo-17,14-friedolanosta-14,22,24-trien-26-oic acid (3) and another new triterpene (24E)-9α-hydroxy-3-oxo-17,14-friedolanosta-14,24-dien-26-oic acid (4) derived from pericarp; a combination of compound 3 and the new isolated triterpene methyl (24E)-9α,23-dihydroxy-3-oxo-17,14- friedolanosta-14,24-dien-26-oate (5), triacylglycerols, friedelin, squalene and a mixture of β-sitosterol and stigmasterol accrued from the outer covering of the stalk; compound 2, caryophyllene, α-carotene and chlorophyll a originating from the leaves; compound 2 and a blend of β-sitosterol and stigmasterol from the blooms; δ-tocotrienol, squalene and triacylglycerols from the mesocarp; and triacylglycerols and a composite of stigmasterol and β-sitosterol recovered from the seeds of G. benthamii. The molecular orientation of compound 1 was characterized by comprehensive 1D and 2D NMR examinations while compounds 2-5 were elucidated by 1D NMR spectroscopy since a new triterpene 4 was observed to have a small difference with compound 3 in C-22 and compound 5 was observed to have a difference with the C-3 signal of compound 2. To further examine the possible bioactivities of the friedolanostanes especially the new molecules, the anti-inflammatory potential of these compounds was predicted through docking analysis in Autodock Vina. Four of the identified friedolanostanes (2-5) were found to have higher binding affinities to NF-κB p50 homodimer than the control dexamethasone. Considering all the probable interactions of 9 amino acid residues, (Arg 57, Tyr 60, Glu 63, Lys 244, Pro 246, Lys 275, Arg 308, Gln 309 and Phe 310) perceivable binding mechanisms were observed to actively interact with the compounds either by conventional hydrogen bonding or by van der Waals forces. Further confirmation from the molecular dynamics study revealed that the stability of the protein-ligand complexes with compounds 2-5 had no significant conformational changes in the structure of the p50 homodimer. Hence, this study provided a chemical profile of the DCM extract obtained from the plant and propose a potential anti-inflammatory activity of the friedolanostanes through in silico investigation. Friedolanostanes (2-5)with promising anti-inflammatory activity may be synthesized and subjected to in vitro and in vivo investigation to establish the anti-inflammatory properties.