Investigation of PDE5/PDE6 and PDE5/PDE11 selective potent tadalafil-like PDE5 inhibitors using combination of molecular modeling approaches, molecular fingerprint-based virtual screening protocols and structure-based pharmacophore development

Abstract

The essential biological function of phosphodiesterase (PDE) type enzymes is to regulate the cytoplasmic levels of intracellular second messengers, 3′,5′-cyclic guanosine monophosphate (cGMP) and/or 3′,5′-cyclic adenosine monophosphate (cAMP). PDE targets have 11 isoenzymes. Of these enzymes, PDE5 has attracted a special attention over the years after its recognition as being the target enzyme in treating erectile dysfunction. Due to the amino acid sequence and the secondary structural similarity of PDE6 and PDE11 with the catalytic domain of PDE5, first-generation PDE5 inhibitors (i.e. sildenafil and vardenafil) are also competitive inhibitors of PDE6 and PDE11. Since the major challenge of designing novel PDE5 inhibitors is to decrease their cross-reactivity with PDE6 and PDE11, in this study, we attempt to identify potent tadalafil-like PDE5 inhibitors that have PDE5/PDE6 and PDE5/PDE11 selectivity. For this aim, the similarity-based virtual screening protocol is applied for the “clean drug-like subset of ZINC database” that contains more than 20 million small compounds. Moreover, molecular dynamics (MD) simulations of selected hits complexed with PDE5 and off-targets were performed in order to get insights for structural and dynamical behaviors of the selected molecules as selective PDE5 inhibitors. Since tadalafil blocks hERG1 K channels in concentration dependent manner, the cardiotoxicity prediction of the hit molecules was also tested. Results of this study can be useful for designing of novel, safe and selective PDE5 inhibitors.

The first‐generation phosphodiesterase 5 inhibitors and their pharmacokinetic issue

“…PDE5 is the predominant member present in the corpora cavernosa, and sildenafil, vardenafil, tadalafil, and avanafil mainly target PDE5, although all PDE5is exert some inhibitory activities against other PDEs at clinical doses, and this may contribute to both efficacy and adverse events. Thus, the mechanisms of action of different PDE5i compounds are similar but not identical (Kayık et al ., ; Scaglione et al ., ). However, the difference between first generation and second generation of PDE5is is not based on a difference in their specificity (see Table ).…”

Sildenafil beyond erectile dysfunction and pulmonary arterial hypertension: Thinking about new indications

“…The visual side effects (functional blindness, blue and blurred vision, and enhanced light sensitivity) caused by sildenafil are indeed retinal in origin and attributed to be competitive inhibitors of PDE6 due to the similarity of amino acid sequence and the secondary structure in catalytic site. PDE6 enzyme is the key effector enzyme for the visual transduction cascade in the retina of mammalian eyes and its location in photoreceptor cells [187,188].…”

Tadalafil: 15 years' journey in male erectile dysfunction and beyond

“…It is worth mentioning that compound ( 10 ) showed remarkable activity against PDE 11A (IC 50 = 11 nM), the exact mechanism of this inhibitory activity is still unknown. More recent studies adopted in silico approaches including molecular modeling and virtual screening protocols to design tadalafil analogues with better PDE5/PDE11 selectivity profile (Kayık, Tüzün, & Durdagi, ). Findings of those studies went along with Abadi et al results indicating PDE5/PDE11 selectivity is governed by the tetracycle terminal ring interactions rather than the substitution on the pendant aryl (Mohamed et al, ).…”