TITLE

Pharmacophore modeling and 3D-QSAR analysis of phosphoinositide 3-kinase p110α inhibitors

AUTHOR(S)
Li, Yiping; Wang, Yawen; Zhang, Fuqiang
PUB. DATE
September 2010
SOURCE
Journal of Molecular Modeling;Sep2010, Vol. 16 Issue 9, p1449
SOURCE TYPE
Academic Journal
DOC. TYPE
Article
ABSTRACT
Pharmacophore modeling studies were undertaken for a series of compounds belonging several groups of phosphoinositide 3-kinase (PI3K) p110α inhibitors: 4-morpholino-2-phenylquinazolines derivatives, pyrido[3′,2′:4,5]furo-[3,2-d]pyrimidine derivatives, imidazo[1,2-a]pyridine derivatives, sulfonylhydrazone substituted imidazo[1,2-a]pyridines, and LY294002. A five-point pharmacophore with three hydrogen bond acceptors (A), one hydrophobic group (H), and one aromatic ring (R) as pharmacophore features was developed. The pharmacophore hypothesis yielded a statistically significant 3D-QSAR model, with a correlation coefficient of R2 = 0.95 for training set compounds. The model generated showed excellent predictive power, with a correlation coefficient of Q2 = 0.88 and r = 0.95 for a test set of 14 compounds. Furthermore, the structure–activity relationships of PI3K p110α inhibitors were elucidated and the activity differences between them discussed. Docking studies were also carried out wherein active and inactive compounds were docked into the active site of the PI3K p110α crystal structure to analyze PI3K p110α–inhibitor interactions. The results provide insights that will aid optimization of these classes of PI3K p110α inhibitors for better activity, and may prove helpful for further lead optimization and virtual screening.
ACCESSION #
52692104

 

Related Articles

  • Combined Structure-Based Pharmacophore and 3D-QSAR Studies on Phenylalanine Series Compounds as TPH1 Inhibitors. Ouyang, Liang; He, Gu; Huang, Wei; Song, Xiangrong; Wu, Fengbo; Xiang, Mingli // International Journal of Molecular Sciences;May2012, Vol. 13 Issue 5, p5348 

    Tryptophan hydroxylase-1 (TPH1) is a key enzyme in the synthesis of serotonin. As a neurotransmitter, serotonin plays important physiological roles both peripherally and centrally. In this study, a combination of ligand-based and structure-based methods is used to clarify the essential...

  • MOLECULAR MODELING ANALYSIS OF THE INHIBITION OF MITOCHONDRIAL CYTOCHROME BC1 COMPLEX ACTIVITY BY TOCOL DERIVATIVES. Singh, Awantika; Hauer-Jensen, Martin; Compadre, Cesar M.; Kumar, K. Sree // AIP Conference Proceedings;6/10/2011, Vol. 1326 Issue 1, p143 

    The biological functions of vitamin E related compounds have been of interest in biomedical research for several decades. Among those compounds, α-, [phonetic_beta]-, δ-, and γ-tocopherols and their oxidation products, α-, [phonetic_beta]-, δ-, γ-tocopherylquinone and their...

  • The Non-Diaryl Heterocycle Classes of p38 MAP Kinase Inhibitors. Cirillo, Pier F.; Pargellis, Christopher; Regan, John // Current Topics in Medicinal Chemistry;Sep2002, Vol. 2 Issue 9, p1021 

    The p38 mitogen activated protein (MAP) kinase is an integral enzyme involved in the production of a wide variety of pro-inflammatory cytokines from various cell types. The identification of this kinase and of the diaryl imidazole containing inhibitor, SB203580, initiated an intense discovery...

  • Pyridinylimidazole Based p38 MAP Kinase Inhibitors. Jackson, Paul F.; Bullington, James L. // Current Topics in Medicinal Chemistry;Sep2002, Vol. 2 Issue 9, p1011 

    The p38 MAP kinase is thought to be involved in a variety of inflammatory and immunological disorders such as rheumatoid arthritis. The pyridinylimidazole class of compounds was the first to potently inhibit this kinase. Since the original reports of their efficacy, they have become the most...

  • Small Molecule Inhibitors of KDR (VEGFR-2) Kinase: An Overview of Structure Activity Relationships. Boyer, Stephen J. // Current Topics in Medicinal Chemistry;Sep2002, Vol. 2 Issue 9, p973 

    The Kinase insert Domain containing Receptor (KDR), alternatively referred to as VEGFR-2, is a receptor for Vascular Endothelial Growth Factors (VEGFs) and functions as a key regulator of angiogenesis, the process by which new capillaries are created from preexisting blood vessels. The induction...

  • Editorial. Player, Mark R. // Current Topics in Medicinal Chemistry;May2009, Vol. 9 Issue 8, p677 

    The article discusses various reports published within the issue, including one by Paul Shapiro et al on extracellular signal-regulated kinase (ERK), one by Zhulun Wang et al on the interleukin-1 receptor-associated kinase 4 (IRAK-4) and another by Michael K. Ameriks and Jennifer D. Venable on...

  • 3D-QSAR and Docking Studies of 4-morpholinopyrrolopyrimidine Deriva- tives as Potent mTOR Inhibitors. Shao-Teng Wang; Yong Ai; Chu Tang; Fa-Jun Song; Ping-Hua Sun // Letters in Drug Design & Discovery;May2011, Vol. 8 Issue 4, p339 

    No abstract available.

  • Novel Inhibitors of AKT: Assessment of a Different Approach Targeting the Pleckstrin Homology Domain. Meuillet, E. J. // Current Medicinal Chemistry;Jun2011, Vol. 18 Issue 18, p2727 

    No abstract available.

  • PI3K/Akt Signalling Pathway Specific Inhibitors: A Novel Strategy to Sensitize Cancer Cells to Anti-Cancer Drugs. Falasca, Marco // Current Pharmaceutical Design;4/21/2010, Vol. 16 Issue 12, p1410 

    The resistance of many types of cancer to chemotherapies represents the major hurdle in successful cancer treatment. Cancer cells can escape the toxic effect of most commonly used drugs despite their different chemical structure and intracellular targets. The mechanisms underlying the failure of...

Share

Read the Article

Courtesy of THE LIBRARY OF VIRGINIA

Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics