In silico Study of the Inhibitory Effects of Sanguinarine and its Proposed Derivative on Phosphoinositide 3-kinase (PI3K) Isoforms
DOI:
https://doi.org/10.26538/tjnpr/v9i10.29Keywords:
Sanguinarine, Sanguinarine Derivative, Pan phosphatidylinositol 3-kinase inhibitors, Pan phosphatidylinositol 3-kinase isoform, Docking, Breast CancerAbstract
Breast cancer (BC) remains the most commonly diagnosed cancer in women worldwide, with its incidence continuing to rise and often experiences resistance to anticancer drugs. Sanguinarine, a prominent benzophenanthridine alkaloid found in many plants, has garnered attention for its multifaceted antitumor activities, through different mechanisms. This study aims to explore the potential inhibitory effect of Sanguinarine alkaloid (SG) and its proposed structurally modified derivative (SGD), using in silico methods, against the PI3K catalytic subunits (p110α, p110β, p110γ, p110δ). Molecular docking was performed to assess the binding affinities of the studied drugs with various PI3K isoforms, while their drug-likeness and pharmacokinetic (ADMET) properties were predicted using in silico approaches. All analyses were performed in silico, and no laboratory synthesis or biological assays were conducted. Preliminary in silico analyses indicated non-significant interactions between the Sanguinarine alkaloid and all PI3K isoforms, accompanied by unfavorable pharmacokinetic and toxicity predictions in comparison with the reference drug, Alpelisib. However, the derived compound exhibited a pan PI3K inhibitory activity with highly significant (p < 0.05) binding affinities with all PI3K isoforms (p110α, p110β, p110γ, p110δ) and possessed an acceptable pharmacokinetic and toxicity profile compared to the parent alkaloid. These findings concluded that the proposed derivative (SGD) could be a potential candidate for the development of a novel antibreast cancer drug, obtained by targeting PI3K catalytic subunits. Our future objectives include synthesizing the new molecule, characterizing it by NMR, MS, and IR, and conducting in vitro and in vivo investigations
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