Discovery of novel CDK1 inhibitors by combining pharmacophore modeling, QSAR analysis and in silico screening followed by in vitro bioassay

European Journal of Medicinal Chemistry
Mahmoud A Al-Sha'er, Mutasem O Taha

Abstract

Cyclin-dependent kinase 1 (CDK1) is a valid anticancer target. With this in mind we applied a modeling workflow by combining pharmacophore modeling and QSAR analysis followed by in silico screening towards the discovery of novel inhibitory CDK1 scaffolds. Virtual screening identified 10 low micromolar inhibitory leads: 8 from the National Caner Institute (NCI) list of compounds and 2 from our in house list of established drugs and agrochemicals. The most potent NCI hit illustrated anti-CDK1 IC(50) value of 0.83 microM, while the drug hit isoxsuprine illustrated anti-CDK1 IC(50) value of 2.9 microM and the agrochemical hit foramsulfuran showed IC(50) = 3.6 microM. These results demonstrate that our virtual screening protocol is able to identify novel anti-CDK1 leads for subsequent development into potential anticancer agents.

Citations

Apr 30, 2013·Journal of Computer-aided Molecular Design·Tony NgoRenate Griffith
Apr 23, 2013·Journal of Molecular Graphics & Modelling·Mahmoud A Al-Sha'erMutasem O Taha
Sep 10, 2011·Journal of Chemical Information and Modeling·Peter RipphausenJürgen Bajorath
Dec 18, 2013·Journal of Computer-aided Molecular Design·Sawsan AbuhamdahMutasem O Taha
Apr 8, 2014·European Journal of Medicinal Chemistry·Aurora L Carreño OteroVladimir V Kouznetsov
Feb 26, 2016·European Journal of Medicinal Chemistry·Sahil SharmaKunal Nepali
May 23, 2012·Journal of Molecular Graphics & Modelling·Ghadeer A R Y SuaifanMutasem O Taha
Jun 23, 2012·Microbiology·María L Suárez FernándezPaul M Selzer
Apr 23, 2016·Future Medicinal Chemistry·Areej Abuhammad, Mutasem Taha
Jul 27, 2011·Bioorganic & Medicinal Chemistry·Maha Habash, Mutasem O Taha
Apr 13, 2011·European Journal of Medicinal Chemistry·Belal O Al-NajjarMutasem O Taha
Jan 13, 2015·Journal of Molecular Graphics & Modelling·Mutasem O TahaAmjad Qandil
Dec 23, 2016·Journal of Molecular Recognition : JMR·Mahmoud A Al-Sha'erMutasem O Taha
Jul 15, 2017·Current Medicinal Chemistry·Jelica VucicevicJohn B O Mitchell
Dec 15, 2011·Journal of Computer-aided Molecular Design·Rand ShahinMutasem O Taha

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