QSAR, structure-based pharmacophore modelling and biological evaluation of novel platelet ADP receptor (P2Y) antagonist

• Published in: RSC medicinal chemistry Vol. 14; no. 2; pp. 239 - 246
• Main Authors: Al-Najjar, Belal O, Abbas, Manal A, Sibai, Obada A, Saqallah, Fadi G, Al-Kabariti, Aya Y
• Format: Journal Article
• Language: English
• Published: England 22-02-2023
• ISSN: 2632-8682; 2632-8682
• DOI: 10.1039/d2md00285j

P2Y
12
has a key role in platelet aggregation and thrombus formation
via
an ADP-induced platelet activation mechanism. Recently, P2Y
12
antagonists have become of great interest in the clinical management of antithrombotic therapy. In light of this, we explored the pharmacophoric space of P2Y
12
using structure-based pharmacophore modelling. Subsequently, genetic algorithm and multiple linear regression analyses were conducted to select the best combination of physicochemical descriptors and pharmacophoric models to create useful predictive quantitative structure-activity relationship (QSAR) equation (
r
2
= 0.9135,
r
(adj)
2
= 0.9147,
r
(PRESS)
2
= 0.9129, LOF = 0.3553). One pharmacophoric model emerged in the QSAR equation and was validated by analysing receiver operating characteristic (ROC) curves. The model was then used to screen 200 000 compounds from the National Cancer Institute (NCI) database. The top-ranked hits were
in vitro
tested, where their IC
50
's range between 4.20 to 35.00 μM when measured
via
the electrode aggregometry assay. Whilst, the VASP phosphorylation assay showed 29.70% platelet reactivity index for NSC618159, which is superior to that of ticagrelor.
In silico
and
in vitro
discovery of P2Y
12
antagonists utilizing structure-based pharmacophore modelling directed by quantitative structure-activity relationship (QSAR) analysis.