Computational and <i>in vitro</i> binding studies of the redesigned pentoxifylline analogue against phosphodiesterases function in sperm

Pentoxifylline (PTX) is a widely used pharmacological agent for the selection of motile sperm in both normozoospermic and asthenozoospermic ejaculates prior to their use in assisted reproductive technologies (ARTs), e.g. intracytoplasmic sperm injection (ICSI). Since cAMP signalling pathways underlie motility, PTX stimulates motility through the inhibition of cAMP-hydrolysing phosphodiesterase (PDE) isoforms in sperm, viz. PDE4A, PDE4D, and PDE10A. However, it has been noted that PTX causes an early acrosome reaction (AR) and has deleterious effects on oocyte development and early embryogenesis. Previous <i>in vitro</i> and <i>in silico</i> binding studies on the aforementioned PDEs with PTX and a modified PTX called PTXm-1 suggested room for improvement in terms of binding affinity. Indeed, using a structure-guided <i>in silico</i> approach we designed a novel modified PTX (mPTX), which outperformed both PTX and PTXm-1 in binding to PDEs in our <i>in silico</i> binding studies based on docking and molecular dynamics (MD) as well as <i>in vitro</i> binding studies employing isothermal titration calorimetry (ITC). Our findings warrant comparative <i>ex vivo</i> evaluation of mPTX to know whether mPTX is more effective than PTX and PTXm-1 vis-à-vis functional competence for assisted reproductive technology.