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Imidazole-containing farnesyltransferase inhibitors: 3D quantitative structure–activity relationships and molecular docking

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Abstract

One of the most promising anticancer and recent antimalarial targets is the heterodimeric zinc-containing protein farnesyltransferase (FT). In this work, we studied a highly diverse series of 192 Abbott-initiated imidazole-containing compounds and their FT inhibitory activities using 3D-QSAR and docking, in order to gain understanding of the interaction of these inhibitors with FT to aid development of a rational strategy for further lead optimization. We report several highly significant and predictive CoMFA and CoMSIA models. The best model, composed of CoMFA steric and electrostatic fields combined with CoMSIA hydrophobic and H-bond acceptor fields, had r 2 = 0.878, q 2 = 0.630, and r 2pred  = 0.614. Docking studies on the statistical outliers revealed that some of them had a different binding mode in the FT active site based on steric bulk and available active site space, explaining why the predicted activities differed from the experimental activities.

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Acknowledgments

Funding from National Center for Zoonotic, Vector-borne, and Enteric Diseases (CK) of the Centers for Disease Control and Prevention (CDC) (U01/CI000211); National Science Foundation (EPS-0556308); University of Mississippi, including from its Office of Research and Sponsored Programs; as well as Laboratory for Applied Drug Design and Synthesis and MCSR computing facilities are greatly appreciated. SP is a Natural Products Neuroscience Fellow [P20 RR021929 from National Center for Research Resources (NCRR), National Institutes of Health (NIH)]. This investigation was conducted in a facility constructed with support from research facilities improvement program C06 RR-14503-01 from the NIH National Center for Research Resources.

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  1. Srinivas Odde

    Present address: Department of Medicinal Chemistry, University of Southern California, Los Angeles, CA, 90089, USA

Authors and Affiliations

  1. Department of Medicinal Chemistry, University of Mississippi, University, MS, 38677-1848, USA

    Aihua Xie, Srinivas Odde, Sivaprakasam Prasanna & Robert J. Doerksen

  2. Research Institute for Pharmaceutical Sciences, University of Mississippi, University, MS, 38677-1848, USA

    Robert J. Doerksen

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  1. Aihua Xie
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Correspondence to Robert J. Doerksen.

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Xie, A., Odde, S., Prasanna, S. et al. Imidazole-containing farnesyltransferase inhibitors: 3D quantitative structure–activity relationships and molecular docking. J Comput Aided Mol Des 23, 431–448 (2009). https://doi.org/10.1007/s10822-009-9278-z

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