QSAR studies on CCR2 antagonists with chiral sensitive hologram descriptors Pramod C. Nair, K. Srikanth and M. Elizabeth Sobhia * Centre for Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, S.A.S. Nagar, Punjab 160062, India Received 17 September 2007; revised 18 December 2007; accepted 8 January 2008 Available online 11 January 2008 Abstract—Chemokines are small molecular weight water-soluble proteins playing a key role in immunomodulation and host-defense mechanisms. CCR2 receptor is targeted for diseases like arthritis, multiple sclerosis, vascular disease, obesity, and type 2 diabetes. Reported, herein are the QSAR studies performed on a diverse set of enantiopure analogues reported as CCR2 antagonists by holo- gram analysis. The best model highlights the importance of chirality feature in comparison with the other models developed without the chirality. The validated model showed high internal and external predictive power. The robustness of the model was achieved with good statistical r 2 of 0.945 and cross-validated r 2 cv of 0.837. The challenging test predictivity of the model was confirmed with r 2 pred of 0.807. The fragment fingerprints help in understanding essential pharmacophoric features for CCR2 antagonism and provide basis for SAR of the molecules. The 2D contribution maps with fragment information will be useful for the design of novel CCR2 antagonists having improved efficacy. Ó 2008 Elsevier Ltd. All rights reserved. Chemokines are small molecular weight water-soluble proteins playing a key role in immunomodulation and host-defense mechanisms. They selectively recruit mono- cytes, lymphocytes and granulocytes like neutrophils to sites of vascular injury, and inflammation. 1–3 About 50 human chemokines are known and divided into four families based on the differences in their structure and function. 2 Their structural classification is based on their distinctiveness such as small size and the occurrence of four cysteine residues in conserved locations forming their 3-dimensional shape. CC chemokines fall under the largest family of chemokines and are named in such a way that the first two of the four cysteine residues in these molecules are next to each other. 2 They are en- coded on chromosome 17 and attract mononuclear cells to sites of chronic inflammation. 1–3 The CC family consists of several CC receptors of which CCR2 is the primary receptor for Monocyte Chemoattractant Pro- tein-1(MCP-1), the most characterized protein, also known as ‘chemokine ligand CCL2’. Binding of CCL2 to CCR2 triggers a number of responses including intra- cellular calcium mobilization, cytoskeletal rearrange- ment, MAP kinase activation, chemotaxis, and degranulation. 4,5 CCL2 and CCR2 knockout mice under a broad range of stimuli show deficient monocyte recruit- ment thus suggesting its potential role in inflammation. 2 Recently researchers have also found that obesity and insulin resistance are linked by CCL2 which induces inflammatory response (macrophage infiltration) in fatty tissues. 3,6,7 All these studies indicate the potential role of CCL2 in obesity, diabetes, and other disease conditions linked via an inflammatory pathway. 3,6–8 As there is no crystal structure information available for CCR2 we have adopted ligand-based approach which is more valuable in the present study. QSAR studies are more often used as a tool for lead optimization within the congeneric domain of molecules, but there are re- ports of its applicability in diverse chemical space for identifying leads. 9–13 Chirality is one of the primary as- pects showing influence on the properties of compounds. And often different biological activities are exhibited for compounds with same structural formulas. Here we re- port the results of holographic QSAR studies performed on diverse set of chiral CCR2 antagonists. The primary objective of the present study is to develop a robust HQSAR model for predicting the CCR2 antagonistic activity for the molecules with similar descriptor proper- ties and to explore the fragment features to gain insight into CCR2 antagonism. 0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2008.01.023 Keywords: Chemokines; Enantiopure; CCR2; HQSAR; Fragments. * Corresponding author. Tel.: +91 172 2211343; fax: +91 172 2214692; e-mail: mesophia@niper.ac.in Available online at www.sciencedirect.com Bioorganic & Medicinal Chemistry Letters 18 (2008) 1323–1330