A GIBAC-based selectivity strategy for the design of PDE5 inhibitors to minimize visual disturbances

Abstract

Phosphodiesterase type 5 (PDE5) inhibitors are widely used in the treatment of various conditions, including erectile dysfunction and pulmonary hypertension. Despite their clinical efficacy, these drugs quite often cause visual disturbances due to off-target effects on Phosphodiesterase type 5 (PDE6) in the retina. This review explores the application of a general intermolecular binding affinity calculator (GIBAC)-based binding selectivity strategy in the design of PDE5 inhibitors, aiming to enhance binding selectivity and minimize visual side effects. This GIBAC strategy integrates computational structural biological approaches to iteratively refine drug-target binding affinities, thereby improving target specificity and the structural biophysical limit for the efficacy-safety balance of PDE5 inhibitors. Through detailed analysis of PDE5’s and PDE6’s biological role and the molecular mechanisms underlying visual disturbances, this article underscores the necessity of target binding selectivity in PDE5 inhibitor design in future. Additionally, this article discusses the practical applications of GIBAC in computational drug discovery and design, along with the future directions and the potential for GIBAC to transform PDE5 inhibitor development, ultimately enhancing therapeutic outcomes and patient safety. Finally, this article calls for a GIBAC-based paradigm shift in computational drug discovery and design towards the continued development of the pharmaceutical industry.

A one-dimensional semaglutide-GLP-1R-based mini static GIBAC

“…First, high binding affinity typically correlates with increased efficacy, i.e., the drug can effectively modulate the target's activity at lower concentrations [22][23][24][25][26][27][28]. Second, a structural biophysical understanding of the intermolecular binding affinity helps in optimizing the potency and selectivity of drug candidates, reducing off-target effects and adverse reactions [29][30][31][32][33][34].…”