The Endocannabinoid System (ECS) is vital for human physiology, and genetic variation within its components can alter function and therapeutic responses. The genetically diverse Moroccan population offers a unique opportunity for pharmacogenomic insight. This study performs a comprehensive genomic analysis of 11 core ECS genes in 109 Moroccan individuals, identifying 170 novel variants. We then performed a deep in silico functional characterization of a novel, high-confidence CNR1 variant (V392A). Extensive, triplicate 500 ns molecular dynamics (MD) simulations were conducted on both the wild-type (WT) and mutant (MT) CB1 receptor. The simulations revealed that the V392A mutation induces significant structural destabilization, evidenced by increased RMSD/RMSF, a consistent loss of α-helicity, and altered interhelical distances crucial for G-protein coupling. Free Energy Landscape (FEL) analysis confirmed the mutant receptor occupies a broader, higher-energy conformational state. This "genomics-to-function" pipeline demonstrates that the Moroccan population harbors significant novel ECS genetic diversity and that the unique V392A CNR1 variant impairs CB1 receptor stability, suggesting a potential for altered signaling and pharmacological responses.
Abbou et al. (Thu,) studied this question.