Computational, biochemical and evaluation of xanthine derivatives against phosphodiesterases to enhance the sperm motility.

Enhancing sperm motility has immensely benefited assisted conception methods. Phosphodiesterases (PDE) break the second messenger cAMP, and therefore, inhibition of their catalytic activity enhances the sperm motility through maintaining cAMP homeostasis in sperm. In view of identifying the molecules that could inhibit PDE functioning in spermatozoa, we aimed to evaluate the phosphodiesterase inhibitors (PDEI) - xanthine derivatives - acefylline, dyphylline and proxyphylline to repurpose them for assisted reproductive technology. These are available in the market as pharmaceutical agents to treat mainly respiratory system diseases. Based on the structure guided studies, we predicted that these molecules bind to the cAMP binding catalytic pocket of PDE enzymes, and further molecular dynamics simulation analysis indicated that these molecules form the stable complexes. Isothermal titration calorimetry studies revealed that acefylline has better affinity towards PDE4A, PDE4D and PDE10A, when compared to dyphylline and proxyphylline. In addition, studies corroborated binding studies that acefylline has much superior sperm motility enhancement property on human ejaculated spermatozoa and mouse testicular spermatozoa compared to dyphylline and proxyphylline.Communicated by Ramaswamy H. Sarma.