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

Abstract

Enhancing sperm motility in vitro 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 in silico 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, ex vivo studies corroborated in vitro 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

Keywords:

• Phosphodiesterase inhibitors
• sperm motility
• assisted reproductive technology
• xanthine derivatives
• isothermal titration calorimetry

Acknowledgements

E.R. thanks the Department of Biotechnology (DBT) and the Science and Engineering Research Board, the Department of Science and Technology, the Government of India for the Ramalingaswami re-entry fellowship and the Early Career Research Award, respectively. M.S. and K.N. thank the Ministry of Human Resource Development, Government of India for the fellowship.

Disclosure statement

No potential conflict of interest was reported by the authors.

Author contributions

Mutyala Satish: data curation; investigation; visualization, original draft writing and editing. Sandhya Kumari: data curation; investigation; visualization, writing-review and editing. Kulhar Nitin: Investigation. Yashas Kiran Ninjoor: Investigation. Aleena Babu: Investigation. Satish Kumar Adiga: writing-review and editing. Eerappa Rajakumara: Conceptualization; formal analysis; funding acquisition, validation, writing-review and editing. Guruprasad Kalthur: Conceptualization; formal analysis; funding acquisition, validation, writing-review and editing.

Correction Statement

This article has been corrected with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This work was supported by the core research grant funded by SERB, DST, Government of India (ID: CRG/2020/001062) and E.R supported by the intramural fund from the Indian Institute of Technology Hyderabad.