Anti-inflammatory pregnene steroids from the oleo-gum resin of Commiphora mukul: in-vitro and in-silico studies

Phytochemical investigation of a methanolic extract derived from the oleo-gum resin of Commiphora mukul resulted in the isolation of seven pregnene-type steroids (1-7), including a new compound named commukulsterol A (1). Their structures were decided by extensive analyses of 1D, 2D-NMR and Mass spectra. The relative configurations of commukulsterols A (1) and B (2) were determined via DFT calculations of their ¹H and ¹³C chemical shifts, followed by DP4+ statistical analysis. Absolute configurations were then decided by biogenetic similarities and specific rotations. Such analyses led to the revision of the structure of 2, initially elucidated as 20S-acetyloxy-4-pregnene-3,16-dione, to pro-20R. 1-7 showed varying inhibitory effects on LPS-induced NO release in RAW264.7 macrophages, with IC₅₀ values ranging from 7.6 to 53.9 μM for (1-6), while 7 didn’t show activity up to 100 μM. On the other hand, molecular docking revealed that 3 & 4 could bind to the catalytic site of inducible nitric oxide synthase (iNOS). Moreover, molecular dynamics simulation of 3 & 4 in association with iNOS were examined for 200 ns, revealing adequate stability. ADMET analysis indicated good oral bioavailability and drug-like properties. The observed chemical profile highlighted a unique chemical relationship between Burseraceae and Simaroubaceae families.