Structure-based redesigning of pentoxifylline analogs against selective phosphodiesterases to modulate sperm functional competence for assisted reproductive technologies

Abstract Phosphodiesterase (PDE) inhibitors, such as pentoxifylline (PTX), are used as pharmacological agents to enhance sperm motility in assisted reproductive technology (ART), mainly to aid the selection of viable sperm in asthenozoospermic ejaculates and testicular spermatozoa, prior to intracyt...

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Autores principales:	Mutyala Satish, Sandhya Kumari, Waghela Deeksha, Suman Abhishek, Kulhar Nitin, Satish Kumar Adiga, Padmaraj Hegde, Jagadeesh Prasad Dasappa, Guruprasad Kalthur, Eerappa Rajakumara
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6b92d4ccba4c4906872030c4e4ff86cb
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spelling	oai:doaj.org-article:6b92d4ccba4c4906872030c4e4ff86cb2021-12-02T17:47:03ZStructure-based redesigning of pentoxifylline analogs against selective phosphodiesterases to modulate sperm functional competence for assisted reproductive technologies10.1038/s41598-021-91636-y2045-2322https://doaj.org/article/6b92d4ccba4c4906872030c4e4ff86cb2021-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-91636-yhttps://doaj.org/toc/2045-2322Abstract Phosphodiesterase (PDE) inhibitors, such as pentoxifylline (PTX), are used as pharmacological agents to enhance sperm motility in assisted reproductive technology (ART), mainly to aid the selection of viable sperm in asthenozoospermic ejaculates and testicular spermatozoa, prior to intracytoplasmic sperm injection (ICSI). However, PTX is reported to induce premature acrosome reaction (AR) and, exert toxic effects on oocyte function and early embryo development. Additionally, in vitro binding studies as well as computational binding free energy (ΔGbind) suggest that PTX exhibits weak binding to sperm PDEs, indicating room for improvement. Aiming to reduce the adverse effects and to enhance the sperm motility, we designed and studied PTX analogues. Using structure-guided in silico approach and by considering the physico-chemical properties of the binding pocket of the PDEs, designed analogues of PTX. In silico assessments indicated that PTX analogues bind more tightly to PDEs and form stable complexes. Particularly, ex vivo evaluation of sperm treated with one of the PTX analogues (PTXm-1), showed comparable beneficial effect at much lower concentration—slower AR, higher DNA integrity and extended longevity of spermatozoa and superior embryo quality. PTXm-1 is proposed to be a better pharmacological agent for ART than PTX for sperm function enhancement.Mutyala SatishSandhya KumariWaghela DeekshaSuman AbhishekKulhar NitinSatish Kumar AdigaPadmaraj HegdeJagadeesh Prasad DasappaGuruprasad KalthurEerappa RajakumaraNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mutyala Satish Sandhya Kumari Waghela Deeksha Suman Abhishek Kulhar Nitin Satish Kumar Adiga Padmaraj Hegde Jagadeesh Prasad Dasappa Guruprasad Kalthur Eerappa Rajakumara Structure-based redesigning of pentoxifylline analogs against selective phosphodiesterases to modulate sperm functional competence for assisted reproductive technologies
description	Abstract Phosphodiesterase (PDE) inhibitors, such as pentoxifylline (PTX), are used as pharmacological agents to enhance sperm motility in assisted reproductive technology (ART), mainly to aid the selection of viable sperm in asthenozoospermic ejaculates and testicular spermatozoa, prior to intracytoplasmic sperm injection (ICSI). However, PTX is reported to induce premature acrosome reaction (AR) and, exert toxic effects on oocyte function and early embryo development. Additionally, in vitro binding studies as well as computational binding free energy (ΔGbind) suggest that PTX exhibits weak binding to sperm PDEs, indicating room for improvement. Aiming to reduce the adverse effects and to enhance the sperm motility, we designed and studied PTX analogues. Using structure-guided in silico approach and by considering the physico-chemical properties of the binding pocket of the PDEs, designed analogues of PTX. In silico assessments indicated that PTX analogues bind more tightly to PDEs and form stable complexes. Particularly, ex vivo evaluation of sperm treated with one of the PTX analogues (PTXm-1), showed comparable beneficial effect at much lower concentration—slower AR, higher DNA integrity and extended longevity of spermatozoa and superior embryo quality. PTXm-1 is proposed to be a better pharmacological agent for ART than PTX for sperm function enhancement.
format	article
author	Mutyala Satish Sandhya Kumari Waghela Deeksha Suman Abhishek Kulhar Nitin Satish Kumar Adiga Padmaraj Hegde Jagadeesh Prasad Dasappa Guruprasad Kalthur Eerappa Rajakumara
author_facet	Mutyala Satish Sandhya Kumari Waghela Deeksha Suman Abhishek Kulhar Nitin Satish Kumar Adiga Padmaraj Hegde Jagadeesh Prasad Dasappa Guruprasad Kalthur Eerappa Rajakumara
author_sort	Mutyala Satish
title	Structure-based redesigning of pentoxifylline analogs against selective phosphodiesterases to modulate sperm functional competence for assisted reproductive technologies
title_short	Structure-based redesigning of pentoxifylline analogs against selective phosphodiesterases to modulate sperm functional competence for assisted reproductive technologies
title_full	Structure-based redesigning of pentoxifylline analogs against selective phosphodiesterases to modulate sperm functional competence for assisted reproductive technologies
title_fullStr	Structure-based redesigning of pentoxifylline analogs against selective phosphodiesterases to modulate sperm functional competence for assisted reproductive technologies
title_full_unstemmed	Structure-based redesigning of pentoxifylline analogs against selective phosphodiesterases to modulate sperm functional competence for assisted reproductive technologies
title_sort	structure-based redesigning of pentoxifylline analogs against selective phosphodiesterases to modulate sperm functional competence for assisted reproductive technologies
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/6b92d4ccba4c4906872030c4e4ff86cb
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Structure-based redesigning of pentoxifylline analogs against selective phosphodiesterases to modulate sperm functional competence for assisted reproductive technologies

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