ORIGINAL PAPER A selectivity study on mTOR/PI3Kα inhibitors by homology modeling and 3D-QSAR Ting Ran & Tao Lu & Haoliang Yuan & Haichun Liu & Jian Wang & Weiwei Zhang & Ying Leng & Guowu Lin & Shulin Zhuang & Yadong Chen Received: 23 December 2010 / Accepted: 9 March 2011 / Published online: 27 April 2011 # Springer-Verlag 2011 Abstract The phosphatidylinositol-3-kinase (PI3K)/Akt/ mammalian target of rapamycin (mTOR) signaling pathway plays a critical role in the regulation of cellular growth, survival and proliferation. mTOR and PI3K have attracted particular attention as cancer targets. These kinases belong to the phosphatidylinositol-3-kinase-related kinase (PIKK) family and therefore have considerable homology in their active sites. To accelerate the discovery of inhibitors with selective activity against mTOR and PI3K as cancer targets, in this work, a homology model of mTOR was developed to identify the structural divergence in the active sites between mTOR and PI3Kα. Furthermore, two highly predictive comparative molecular similarity index analyses (CoMSIA) models were built based on 304 selective inhibitors docked into mTOR and PI3Kα, respectively (mTOR: q 2 =0.658, r pre 2 =0.839; PI3Kα: q 2 =0.540, r pre 2 = 0.719). The results showed that steric and electrostatic fields have an important influence on selectivity towards mTOR and PI3Kα—a finding consistent with the structural divergence between the active sites. The findings may be helpful in investigating selective mTOR/PI3Kα inhibitors. Keywords mTOR . PI3Kα . Selectivity . Homology modeling . 3D-QSAR Introduction The PI3K signaling pathway is crucial to many aspects of cell growth and survival via its regulation of widely divergent physiological processes including cell cycle progression, differentiation, transcription, translation and apoptosis [1]. Dysregulation, either through amplification of PI3K, deletion of PTEN (phosphatase and tensin homology protein) or activating mutations, has been linked closely to the development and progression of a wide range of hyper proliferative diseases and cancers [2]. This has prompted intense interest in the development of small molecule modulators of key proteins in this signaling cascade. PI3Ks are lipid kinases that regulate cellular growth and metabolism by phosphorylation of the 3-hydroxy of phospha- tidylinositol to generate phosphatidylinositol triphosphate (PIP3) [3, 4]. Among different subtypes of PI3Ks, PI3Kα is the primary target for the treatment of cancers since functional loss of PTEN (the most commonly mutated tumor-suppressor gene in cancer after p53), oncogenic mutations and amplification of the PIK3CA gene (which encodes PI3Kα), and over-expression of Akt have been established in many human cancers [5]. mTOR is a serine/threonine protein kinase that exists as two functional protein complexes mTORC1 and mTORC2 [6, 7]. This kinase is the main downstream component of Electronic supplementary material The online version of this article (doi:10.1007/s00894-011-1034-3) contains supplementary material, which is available to authorized users. T. Ran : T. Lu : H. Yuan : H. Liu : J. Wang : W. Zhang : Y. Leng : G. Lin : Y. Chen (*) Laboratory of Molecular Design and Drug Discovery, College of Basic Science, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China e-mail: ydchen@cpu.edu.cn S. Zhuang Institute of Environmental Science, Zhejiang University, 388 Yuhangtang Road, Hangzhou 310058, China J Mol Model (2012) 18:171–186 DOI 10.1007/s00894-011-1034-3