Insilico Investigation of Terpenoid efficacy on Cannabinoid Receptors using QSAR models and fragment-based Pharmacophore modelling

Cannabis Sativa a medical plant rich in phytochemicals have a range of terpenoids and cannabinoids with a wide range of therapeutic uses. The possible interaction of terpenoids with cannabinoid receptors implicated in analgesic pathways has not received enough attention. This work used in silico methods to target Cannabinoid Receptors Type I (CNR1) and II (CNR2) in order to find novel terpenoid compounds from Cannabis sativa that may have pain-relieving properties. QSAR modelling based on known cannabinoid receptor inhibitors was used to build and screen a curated library of 119 terpenoids. The terpenoid library was screened using pharmacophore models that were created. Molecular docking was performed on the top candidates using CNR1 (PDB: 5U09) and CNR2 (PDB: 5ZTY). To evaluate the stability of receptor-ligand complexes over 100 ns, molecular dynamics simulations were run. SwissADME was used for ADMET profiling in order to assess drug-likeness and pharmacokinetic characteristics. Both receptors QSAR models showed strong predictive power (CNR1: r2 = 0.854; CNR2: r2 = 0.798). {gamma}-Eudesmol and Bisabolol were the top hits for CNR1 and CNR2, respectively, according to pharmacophore screening. Strong binding affinities were demonstrated by molecular docking ({gamma}-Eudesmol: -7.9 kcal/mol; Bisabolol: -8.5 kcal/mol), and simulations verified the stable connections. Both compounds were drug-like, according to ADMET analysis, while {gamma}-Eudesmol had better synthetic accessibility and fewer structural alarms. According to the results, bisabolol and {gamma}-Eudesmol show promise as cannabinoid receptor-targeted analgesics. The finding encourages more biological validation and emphasises the potential of terpenoids obtained from Cannabis sativa in medicinal medication discovery. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/674146v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@3e2544org.highwire.dtl.DTLVardef@cefborg.highwire.dtl.DTLVardef@114cf19org.highwire.dtl.DTLVardef@128b069_HPS_FORMAT_FIGEXP M_FIG C_FIG