Identification of selective inhibitors for phosphodiesterase 5A using e-pharmacophore modelling and large-scale virtual screening-based structure guided drug discovery approaches
Creators: name: Maryam, Arooma
name: Siddiqi, Abdul Rauf
name: Vedithi, Sundeep Chaitanya
name: Ece, Abdulilah
name: Khalid, Rana Rehan
Publisher: name: Taylor & Francis
Year: 2023
Subjects: subject: Biophysics
subject: Biochemistry
subject: Cell Biology
subject: Pharmacology
subject: Chemical Sciences not elsewhere classified
subject: Biological Sciences not elsewhere classified
subject: Information Systems not elsewhere classified
subject: Cancer
subject: Infectious Diseases
subject: FOS: Health sciences

description: The inhibition of Phosphodiesterase 5A (PDEA5) has the potential to modulate pulmonary arterial hypertension and cardiovascular diseases. Exploring the cross-reactivity of clinically available PDE5A therapeutics with PDE6A is intriguing in order to develop highly selective PDE5A compounds in cardiovascular arena. In the current study, we leveraged e-pharmacophore based screening and molecular dynamics (MD) simulation to discover more selective PDE5A inhibitors as compared to the PDE6A catalytic domain. e-Pharmacophore based mapping of the CoCoCo database (7 million compounds: ∼ 150,000,000 conformers), followed by Glide docking, MM-GBSA, and protein–inhibitor interaction analysis, revealed 1536427, 4832637 and 6788240 as stable, tight binders of PDE5A instead of PDE6A. These compounds adhere to Lipinski Rule of Five (RO5) and ADME/Tox criteria. MD simulations analysis showed that 1536427 stays stable and tightly binds to catalytic (Q-region) core of PDE5A catalytic domain as compared to sildenafil. Pronounced inward motions of the hydrophobic (H-region) and Lid region indicate the closure of PDE5A-1536427 complex, whereas this region in PDE6A-1536427 is more open. Significant differences in the interactions, stability, and dynamics of 1536427 were observed in the catalytic domain of PDE6A, demonstrating less specificity for PDE6A in comparison to PDE5A. After lead optimization and therapeutic interventions, this proposed lead may emerge as a promising PDE5A selective inhibitor. Communicated by Ramaswamy H. Sarma This study proposes PDE5A selective compounds to cure pulmonary arterial hypertension and cardiovascular diseases. An exhaustive search of chemical databases has been done by applying structure-based pharmacophore-based, ADMET screening, molecular dynamics (MD) simulations, and essential dynamics analysis to evaluate the selectivity of five proposed compounds for PDE5A over the PDE6A variant. Ultimately, we put forward one compound as a potent inhibitor solely for PDE5A, relying on the interaction of key catalytic residues. These interactions initiate a pronounced involvement of core structural regions, ensuring the tight binding of the inhibitor within the PDE5A catalytic region. In contrast, significant differences were observed in terms of the binding of this compound in the PDE6A catalytic domain. The structural findings presented in this study can serve as a good starting point for experimental efforts to develop selective PDE5A inhibitors with minimal side effects.