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Biological evaluation and docking studies of recently identified inhibitors of phosphoinositide-3-kinases.

ABSTRACT: The alpha isoform of the phosphatidylinositol-3-kinases (PI3K?) is often mutated, amplified and overexpressed in human tumors. In an effort to develop new inhibitors targeting this enzyme, we carried out a pharmacophore model study based on six PI3K?-selective compounds. The pharmacophore searching identified three structurally novel inhibitors of PI3K? and its H1047R mutant. Our biological studies show that two of our hit molecules suppressed the formation of pAKT, a downstream effector of PI3K?, and induced apoptosis in the HCT116 colon cancer cell line. QPLD-based docking showed that residues Asp933, Glu849, Val851, and Gln859 appeared to be key binding residues for active inhibitors.

SUBMITTER: Sabbah DA

PROVIDER: S-EPMC4472446 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Biological evaluation and docking studies of recently identified inhibitors of phosphoinositide-3-kinases.

Sabbah Dima A DA Simms Neka A NA Brattain Michael G MG Vennerstrom Jonathan L JL Zhong Haizhen H

Bioorganic & medicinal chemistry letters 20111213 2

The alpha isoform of the phosphatidylinositol-3-kinases (PI3Kα) is often mutated, amplified and overexpressed in human tumors. In an effort to develop new inhibitors targeting this enzyme, we carried out a pharmacophore model study based on six PI3Kα-selective compounds. The pharmacophore searching identified three structurally novel inhibitors of PI3Kα and its H1047R mutant. Our biological studies show that two of our hit molecules suppressed the formation of pAKT, a downstream effector of PI3K ...[more]

PMID: 22212721

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Project description:Non-steroidal anti-inflammatory drugs (NSAIDs) are considered one of the most commonly used medications globally. Seventeen isoxazole-containing compounds with various functional groups were evaluated in this work to identify which one was the most potent and which group was most selective toward COX-1 and COX-2 by using an in vitro COX inhibition assay kit. Their cytotoxicity was evaluated on the normal hepatic cell line (LX-2) utilizing the MTS assay. Moreover, these molecules' antibacterial and antifungal activities were evaluated using a microdilution assay against several bacterial and fungal species. In addition, molecular docking studies were conducted to identify the possible binding interactions between these compounds and their biological targets by using the X-ray crystal structure of the human COX enzyme and different proteins of bacterial and fungal strains. At the same time, the QiKProp module was used for ADME-T analysis. The results showed that all evaluated isoxazole derivatives showed moderate to potent activities against COX enzymes. The most potent compound against COX-1 and COX-2 enzymes was A13, with IC50 values of 64 and 13 nM, respectively, and a significant selectivity ratio of 4.63. It was clear that the 3,4-dimethoxy substitution on the first phenyl ring and the Cl atom on the other phenyl pushed the 5-methyl-isoxazole ring toward the secondary binding pocket and created the ideal binding interactions with the COX-2 enzyme in comparison with the other compounds. Compound A8 showed antibacterial and antifungal activities against Pseudomonas aeruginosa, Klebsiella pneumonia, and Candida albicans with MIC values of 2 mg/ml. In fact, this compound showed possible binding interactions with the elastase in P. aeruginosa and KPC-2 carbapenemase in K. pneumonia. Furthermore, for better understanding, molecular dynamics simulations were undertaken to study the change in dynamicity of the protein backbone and ligand after the ligand binds to the protein and to ensure the stability of ligand-protein complexes.Supplementary informationThe online version contains supplementary material available at 10.1007/s13205-022-03408-8.

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Biological evaluation and docking studies of recently identified inhibitors of phosphoinositide-3-kinases.

Publications

Biological evaluation and docking studies of recently identified inhibitors of phosphoinositide-3-kinases.

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