Page 111 - ITPS-7-2

INNOSC Theranostics

and Pharmacological Sciences

ORIGINAL RESEARCH ARTICLE
Rational drug design from phosphatidylinositol

3-kinase-α inhibitors through molecular docking
and 3D-QSAR methodologies for cancer

immunotherapy

2†
1†
Kevin Tochukwu Dibia *, Sandra Nneka Van-Dibia , and
Philomena Kanwulia Igbokwe 1
1 Department of Chemical Engineering, Faculty of Engineering, Nnamdi Azikiwe, University, Awka,
Anambra, Nigeria
2 Department of Animal Physiology, College of Animal Science and Livestock Production, Federal
University of Agriculture, Abeokuta, Ogun, Nigeria

Abstract

Dysregulation or aberrant activation of the phosphatidylinositol 3-kinase (PI3K)
signaling pathway is commonly observed in various cancers and is associated
†These authors contributed equally with tumor growth, metastasis, and resistance to therapy. Targeting PI3K-α with
to the work. appropriate inhibitors can disrupt this pathway, hindering cancer progression, and
*Corresponding author: potentially enhancing the immune system’s ability to recognize and eliminate cancer
Kevin Tochukwu Dibia cells. In this study, we aimed to design a novel and potent inhibitor of PI3K-α for cancer
(tkevin.dibia@gmail.com)
immunotherapy using rational drug design techniques, including virtual screening,
Citation: Dibia KT, Van-Dibia SN, molecular docking, and 3D-QSAR. We obtained the human PI3K-α protein (6PYS)
Igbokwe PK. Rational drug design
from phosphatidylinositol 3-kinase-α complexed with (3S)-3-benzyl-3-methyl-5-[5-(2-methylpyrimidin-5-yl)pyrazolo[1,5-a]
inhibitors through molecular docking pyrimidin-3-yl]-1,3-dihydro-2H-indol-2-one (PJ5) from the RCSB Protein Data Bank.
and 3D-QSAR methodologies for Virtual screening of ligands, integrated with predictive computational molecular
cancer immunotherapy. INNOSC docking and 3D-field-based-QSAR, was implemented using appropriate Schrödinger
Theranostics and Pharmacological
Sciences. 2024;7(2):2340. Maestro modules. Rational drug design was also carried out, and its clinical relevance
doi: 10.36922/itps.2340 was validated across several ADMET descriptors. Docking results suggested that a
Received: November 30, 2023 hybrid of sulfonamide and pyridine-based heterocyclic compounds, functionalized
with potent moieties derived from alkaloids, exhibited adequate synergistic
Accepted: February 1, 2024
biological effects capable of enhancing sufficient biological activity against PI3K-α.
Published Online: April 15, 2024 A field-based 3D-QSAR model was built on four partial least squares factors, and
Copyright: © 2024 Author(s). five statistical metrics were employed to validate the model. The newly designed
This is an Open-Access article ligand from this approach, named 6’-amino-5’-(2-fluoro-1,3-oxazol-5-yl)-N-{[3-
distributed under the terms of the (hydroxymethyl)oxetan-3-yl]methyl}-3-methyl-[2,3’-bipyridine]-6-sulfonamide or T85,
Creative Commons Attribution
License, permitting distribution, exhibited a predicted bioactivity (pIC ) of 8.25. The predicted ADMET properties of
50
and reproduction in any medium, T85 fell reasonably within the range of recommended standards, especially adhering
provided the original work is to Lipinski’s rule of five and Jorgensen’s rule of three. In conclusion, the results of this
properly cited.
study offer significant insights into in silico drug design using a rational approach,
Publisher’s Note: AccScience which could expedite the discovery and development of new drug molecules.
Publishing remains neutral with
regard to jurisdictional claims in
published maps and institutional
affiliations. Keywords: Cancer; PI3K-α; Molecular docking; 3D-QSAR; ADMET

Volume 7 Issue 2 (2024) 1 doi: 10.36922/itps.2340