Quinazoline-2,4(1H,3H)-dione derivatives as new class of CB1 Agonists: A pharmacophore-based virtual screening workflow and drug discovery

<ns3:p> Background The cannabinoid 1 (CB1) receptor is the primary target of Δ <ns3:sup>9</ns3:sup> -tetrahydrocannabinol (Δ <ns3:sup>9</ns3:sup> -THC), the psychoactive component of cannabis sativa (commonly known as “kif” in Morocco). Methods Here, we identified novel CB1 agonists using virtual screening approaches. First, we developed a pharmacophore model based on the known CB1 agonist AM11542 and screened a database of over three million compounds. Molecular docking using AutoDock Vina identified 61 hits with binding affinities of less than -9.00 Kcal/mol. Subsequent ADME-Tox (absorption, distribution, metabolism, excretion, and toxicity) analysis narrowed the selection to 18 promising candidates. Results Among these, three agonists exhibited strong characteristics, including a favorable inhibition constant (Ki) and key hydrogen-bond interactions with critical residues in the CB1 binding pocket: PUBChem157251136 (Ki=2.09 nM), ZINC64438485 (Ki= 0.262 nM) and ZINC64438506 (Ki =0.244 nM). These agonists formed stable hydrogen bonds with CB1 binding pocket residues (Ser383, Ser173, His178 and Thr197). Molecular dynamics simulations (100 ns, GROMACS) demonstrated structural stability (RMSD &lt; 1 nm) and low conformational flexibility (RMSF &lt; 1 nm) for all complexes. MM-GBSA binding free energy calculations further confirmed the thermodynamic stability of all complexes, with interaction energies ranging from -30.59 to -49.98 kcal/mol. These comprehensive simulations confirm that all identified agonist complexes maintain stable binding conformations with optimal interaction profiles characteristic of CB1 receptor activation. Conclusion These results could pave the way for researching and developing new quinazolinz-2, 4(1H, 3H)-Dione derivatives as a new class of CB1 receptor agonists. </ns3:p>