Discovery of New Phosphoinositide 3-kinase Delta (PI3Kδ) Inhibitors via Virtual Screening using Crystallography-derived Pharmacophore Modelling and QSAR Analysis

Medicinal Chemistry
Mahmoud A Al-Sha'erMutasem O Taha

Abstract

PI3Kδ is predominantly expressed in hematopoietic cells and participates in the activation of leukocytes. PI3Kδ inhibition is a promising approach for treating inflammatory diseases and leukocyte malignancies. Accordingly, we decided to model PI3Kδ binding. Seventeen PI3Kδ crystallographic complexes were used to extract 94 pharmacophore models. QSAR modelling was subsequently used to select the superior pharmacophore(s) that best explain bioactivity variation within a list of 79 diverse inhibitors (i.e., upon combination with other physicochemical descriptors). The best QSAR model (r2 = 0.71, r2 LOO = 0.70, r2 press against external testing list of 15 compounds = 0.80) included a single crystallographic pharmacophore of optimal explanatory qualities. The resulting pharmacophore and QSAR model were used to screen the National Cancer Institute (NCI) database for new PI3Kδ inhibitors. Two hits showed low micromolar IC50 values. Crystallography-based pharmacophores were successfully combined with QSAR analysis for the identification of novel PI3Kδ inhibitors.

References

Jul 19, 1996·Journal of Medicinal Chemistry·G W Bemis, M A Murcko
Oct 26, 1999·Journal of Chemical Information and Computer Sciences·M HannN Ramsden
Jul 27, 2001·Current Medicinal Chemistry·Y Kurogi, O F Güner
Mar 30, 2002·Advanced Drug Delivery Reviews·W Patrick Walters, Mark A Murcko
Jan 28, 2003·Biochemical Society Transactions·K Okkenhaug, B Vanhaesebroeck
Apr 2, 2003·Nature Reviews. Immunology·Klaus Okkenhaug, Bart Vanhaesebroeck
Apr 2, 2003·Nature Reviews. Drug Discovery·W Patrick Walters, Mark Namchuk
Jul 11, 2006·Biochemical Pharmacology·Giuseppe Ermondi, Giulia Caron
Oct 6, 2006·The Journal of Pharmacology and Experimental Therapeutics·Kazuhiro ItoIan M Adcock
Dec 8, 2006·Journal of Medicinal Chemistry·Brian K Shoichet
Feb 10, 2007·Nature Reviews. Immunology·Christian RommelHong Ji
Mar 21, 2007·Biochemical Society Transactions·T Crabbe
Nov 8, 2007·Journal of Chemical Information and Modeling·Shashidhar N RaoJudith M LaLonde
Apr 9, 2008·Current Opinion in Pharmacology·Matt Thomas, Charles Owen
Jul 12, 2008·Drug Discovery Today·Andrew M DavisGerard J Kleywegt
Jun 1, 2008·Expert Opinion on Drug Discovery·Haiching MaKurumi Horiuchi
Aug 20, 2009·Medicinal Chemistry·Osvaldo A Santos-FilhoRicardo Bicca de Alencastro
Apr 16, 2010·Journal of Molecular Modeling·B V S Suneel KumarJagarlapudi A R P Sarma
Jul 14, 2011·Molecular Cancer Therapeutics·Jing YuanShubha Bagrodia
Apr 7, 2012·Journal of Chemical Information and Modeling·Jamel MeslamaniDidier Rognan
May 16, 2012·Cancer Discovery·David A Fruman, Christian Rommel
Aug 11, 2012·Journal of Medicinal Chemistry·Jeremy M MurrayDaniel P Sutherlin
Aug 1, 2006·Expert Opinion on Drug Discovery·Thierry Langer, Rémy D Hoffmann
Apr 23, 2013·Journal of Molecular Graphics & Modelling·Mahmoud A Al-Sha'erMutasem O Taha
Nov 12, 2013·Nucleic Acids Research·A Patrícia BentoJohn P Overington
Dec 18, 2013·Journal of Computer-aided Molecular Design·Sawsan AbuhamdahMutasem O Taha
Jan 1, 2014·Journal of Chemical Information and Modeling·Balder LaiChris Oostenbrink

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