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

Scientific Reports
Mutyala SatishEerappa Rajakumara

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  s...Continue Reading

References

Jun 1, 1991·British Journal of Clinical Pharmacology·M R ShenS S Chen
Apr 1, 1990·International Journal of Andrology·L RogbergA Pousette
Oct 1, 1989·Gamete Research·J Tesarik, V Kopecny
Jan 1, 1994·Reproduction, Fertility, and Development·O Lacham-Kaplan, A O Trounson
Jan 17, 2002·The New England Journal of Medicine·D S GuzickUNKNOWN National Cooperative Reproductive Medicine Network
May 16, 2002·Fertility and Sterility·Ira D SharlipRichard Sadovsky
Oct 15, 2003·Fertility and Sterility·María José MunuceLida Morisoli
Sep 24, 2005·Biology of Reproduction·Malini BajpaiDaniel W Carr
Apr 12, 2006·Nature Reviews. Molecular Cell Biology·Michael Eisenbach, Laura C Giojalas
Mar 3, 2007·Nature Cell Biology·Stephen PublicoverChristopher Barratt
Jan 1, 2008·Journal of Human Reproductive Sciences·Adiga SkKumar P
Jan 10, 2012·Journal of Biomolecular Screening·Michael I RechtFrancisco E Torres
Apr 25, 2012·Journal of Assisted Reproduction and Genetics·Guruprasad KalthurSatish K Adiga
Nov 15, 2012·Bioorganic & Medicinal Chemistry Letters·Robert M RzasaJennifer R Allen
Oct 31, 2013·Methods in Molecular Biology·Fabian Sievers, Desmond G Higgins
Jul 30, 2014·Biochimica Et Biophysica Acta·Mariano G BuffoneDario Krapf
Jan 21, 2015·ELife·Vera JansenDagmar Wachten
Jan 10, 2016·European Journal of Obstetrics, Gynecology, and Reproductive Biology·Evrim UnsalVolkan Baltacı
Mar 24, 2016·ELife·Shatanik MukherjeeDagmar Wachten
Nov 12, 2016·Biochimica Et Biophysica Acta. General Subjects·Loïze MaréchalFrançois J Richard
Oct 3, 2017·Urologia·Bihari L MehraVasudevan Jaya
Oct 28, 2017·Biochemical and Biophysical Research Communications·Ann V IsaacRenu Pasricha
Nov 18, 2017·Molecular and Cellular Endocrinology·Melanie BalbachDagmar Wachten
Dec 20, 2017·Advances in Experimental Medicine and Biology·Erma Z Drobnis, Ajay K Nangia
Feb 16, 2019·Journal of Chemical Theory and Computation·Katarina RoosEdward D Harder
Jul 15, 2020·PLoS Biology·Nathalie Percie du SertHanno Würbel
Nov 26, 2020·Reproductive Sciences·Sandhya KumariGuruprasad Kalthur

❮ Previous
Next ❯

Software Mentioned

Origin
OPLS3e
Clustal Omega
ISAS
Skanit
SiteMap
Maestro Suit
GraphPad
MM
GBSA

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.