In Silico Development and Characterization of Nisoldipine Analogues for Enhanced Solubility and Therapeutic Potential in the Treatment of Angina Pectoris.

Abstract

Background: Angina pectoris, a common cardiovascular condition, necessitates the de-velopment of effective therapeutic agents. Nisoldipine, a calcium channel blocker, and its analogues have shown potential in treating this condition. However, the optimization of these compounds for enhanced therapeutic efficacy remains a critical challenge.

Objective: This study aimed to investigate the therapeutic potential of Nisoldipine analogues through in silico analysis, with the goal of identifying lead compounds for the treatment of angina pectoris and optimizing their formulation for improved solubility and drug release.

Methods: Eighteen Nisoldipine derivatives were screened using in silico techniques, including mo-lecular docking, SWISS ADME analysis, and molecular dynamics (MD) simulations. The top candi-date, ZINC26826387, was identified and further analyzed. A comprehensive gene set analysis was performed using OMIM, GeneCards, and STITCH databases to identify target hub genes associated with angina pectoris. PPI network analysis and CytoHubba ranking were used to prioritize key genes for further study. Additionally, the lead compound was optimized through nanoparticle formulation, and the resulting nanoparticle tablets were characterized for solubility, dissolution, particle size, en-trapment efficiency, and zeta potential. ANOVA was used to analyze the characterization data.

Results: ZINC26826387 emerged as the most promising Nisoldipine analogue, exhibiting superior solubility, absence of AMES toxicity, strong molecular docking interaction with the target protein (docking score of -8.0 kcal/mol), and favourable pharmacokinetic properties. MD simulation con-firmed the stability of the ligand-receptor complex. The study also identified 88 target hub genes associated with angina pectoris, with PTGS2 prioritized as a key gene. The nanoparticle formulation of ZINC26826387 significantly enhanced solubility by 2.53-fold compared to the unformulated com-pound. The optimized nanoparticle tablets achieved a 98.53% drug release within 30 minutes, with an average particle size of 50 nm, entrapment efficiency of 98.89%, and zeta potential of -52 mV, indicating good stability and uniformity.

Conclusion: The study demonstrates the therapeutic potential of ZINC26826387, a Nisoldipine ana-logue, through its enhanced solubility and reduced Crystallinity. The lead compound was made into Nanoparticles using Pluronic F407 as carrier. These nanoparticles were further formulated to oral disintegrating tablets for rapid drug release, good stability compared to conventional tablets. These findings suggest that ZINC26826387 could be a promising candidate for the treatment of angina pec-toris.