TY - JOUR
T1 - Structure-based redesigning of pentoxifylline analogs against selective phosphodiesterases to modulate sperm functional competence for assisted reproductive technologies
AU - Satish, Mutyala
AU - Kumari, Sandhya
AU - Deeksha, Waghela
AU - Abhishek, Suman
AU - Nitin, Kulhar
AU - Adiga, Satish Kumar
AU - Hegde, Padmaraj
AU - Dasappa, Jagadeesh Prasad
AU - Kalthur, Guruprasad
AU - Rajakumara, Eerappa
N1 - Funding Information:
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., S.A. and K.N. thank the Ministry of Human Resource Development, Government of India for the fellowship. W.D. thanks University Grants Commission, Government of India for the fellowship.
Funding Information:
E.R and G.K are supported by the core research grant funded by SERB, DST, Government of India (ID: CRG/2020/001062) and supported by the intramural fund from the Indian Institute of Technology Hyderabad to E.R. S.K. thanks Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal for the seed money grant (ID: 00000205).
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41598-021-91636-y
DO - 10.1038/s41598-021-91636-y
M3 - Article
C2 - 34112881
AN - SCOPUS:85107605790
SN - 2045-2322
VL - 11
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 12293
ER -