Designing Small-Molecule Allosteric Inhibitors of CYP2C19 to Prevent Clopidogrel Resistance in Patients With Specific Genetic Polymorphisms

Abstract

Background: Clopidogrel resistance due to CYP2C19 polymorphisms presents a major barrier in achieving effective antiplatelet therapy, particularly in genetically predisposed populations. Current solutions often involve switching to alternative medications, which may be cost-prohibitive or contraindicated. A pharmacological strategy aimed at correcting enzyme dysfunction, rather than altering therapy, offers a novel approach to personalized treatment. Objective: To develop and evaluate a small-molecule allosteric inhibitor of CYP2C19 that enhances clopidogrel activation in individuals with reduced-function genetic variants. Methods: A descriptive study was conducted using computational modeling and pharmacokinetic simulation over eight months in South Punjab. A sample of 384 genotype-simulated participants was generated. Molecular docking and virtual screening techniques were used to identify candidate allosteric inhibitors targeting polymorphic CYP2C19 isoforms. A population-based pharmacokinetic model simulated active clopidogrel metabolite concentrations before and after co-therapy. Statistical analysis was performed using SPSS 26, with paired t-tests and ANOVA applied to normally distributed data. Results: Significant increases in active clopidogrel metabolite concentrations were observed post-intervention in all variant genotypes. Mean improvements were highest in *3/*3 (111.7%) and *2/*2 (79.4%) groups. Paired t-tests confirmed statistical significance in all mutant genotypes (p < 0.001). The intervention demonstrated robust potential to correct metabolic inefficiencies without altering standard antiplatelet therapy. Conclusion: The proposed co-therapy offers a promising solution to genetically driven clopidogrel resistance through targeted CYP2C19 modulation. This strategy could enable personalized, cost-effective, and clinically adaptable antiplatelet treatment in genetically diverse populations.