Please use this identifier to cite or link to this item: http://localhost:8080/xmlui/handle/123456789/7693
Title: New drug-like small molecule antagonizes phosphatidylinositol (3,4,5)-trisphosphate (PIP3) in patients with conotruncal heart defects
Authors: Fayez, Alaaeldin G.
Esmaiel, Nora N.
Ashaat, Engy A.
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Keywords: Akt
Conotruncal heart defects
Drug design
PIP3 antagonist
Pleckstrin homology domain
Signal transduction pathway
Issue Date: 2023
Publisher: Journal of Taibah University Medical Sciences
Series/Report no.: Original Article;1244-1253
Abstract: Objectives: Conotruncal heart defects (CTDs) are highly heritable, and approximately one-third of all congenital heart defects are due to CTDs. Through post-analysis of GWAS data relevant to CTDs, a new putative signal transduction pathway, called Vars2-Pic3ca-Akt, associated with CTD has been hypothesized. Here, we aimed to validate the Vars2- Pic3ca-Akt pathway experimentally by measuring Vars2 and PIP3 in patients with CTDs and controls, and to construct a PIP3 inhibitor, as one of harmful-relevant CTD pathogenesis, through an Akt-based drug design strategy. Methods: rs2517582 genotype and relative Vars2 expression in 207 individuals were determined by DNA sequencing and qPCR respectively, and free plasma PIP3 in 190 individuals was quantified through ELISA. An Akt-pharmacophore feature model was used to discover PIP3 antagonists with multiple computational and druglike estimation tools. Results: CTD pathogenesis due to Vars2-Pic3ca-Akt overstimulation was confirmed by elevated Vars2 and PIP3 in patients with CTDs. We identified a new small molecule, 322PESB, that antagonizes PIP3 binding. This molecule was prioritized via virtual screening of 21 hypothetical small molecules and it showed minimal RMSD change, high binding affinity andlower dissociation constant than PIP3-Akt complex by 1.99 Kcal/Mol, thus resulting in an equilibrium shift toward 322PESB-Akt complex formation. Moreover, 322PESB exhibited acceptable pharmacokinetics and drug likeness features according to ADME and Lipinski’s rule of five classifiers. This compound is the first potential drug-like molecule reported for patients with CTDs with elevated PIP3. Conclusion: PIP3 is a useful diagnostic biomarker for patients with CTDs. The Akt-pharmacophore feature model is a feasible approach for discovery of PIP3 signalling antagonists. Further 322PESB development and testing are recommended.
URI: http://localhost:8080/xmlui/handle/123456789/7693
ISSN: 1658-3612
Appears in Collections:Vol 18 No 6 (2023)

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