ORIGINAL RESEARCH Synergistic application of target structure-based alignment and 3D-QSAR study of protein tyrosine phosphatase 1B (PTP1B) inhibitors Rajesh Singh • M. Elizabeth Sobhia Received: 27 July 2009 / Accepted: 3 May 2010 / Published online: 18 June 2010 Ó Springer Science+Business Media, LLC 2010 Abstract Protein tyrosine phosphatase 1B (PTP1B) has been demonstrated to play a key role in the negative sig- naling pathway of insulin. Potent and orally active PTP1B inhibitors are considered to be promising pharmacological agents for the treatment of type 2 diabetes and resistance to weight gain. CoMFA studies were performed on a set of PTP1B inhibitors, which are known to bind simultaneously to the active site as well as a sub-binding site. An align- ment, based on eight different crystal structure complexes of PTP1B was carried out to study the synergistic appli- cation of the alignment on CoMFA. The CoMFA model with statistical parameters r 2 cv ¼ 0:506; r 2 ncv ¼ 0:985, standard error of estimate 0.12, and F = 244.4 was found to be significant. The steric and electrostatic components presumably play an important role to achieve activity and selectivity in this series of molecules. Keywords Insulin signaling  Diabetes  PTP1B inhibitors  CoMFA alignment  Active site  Sub binding site Introduction Computer-Aided Drug Design (CADD) methods are increasingly gaining importance in diverse facets of drug discovery research to discover novel drug molecules for various diseases. Among CADD methods, 3D-QSAR methods are well known in predicting biological activity of known and unknown compounds, predicting toxic features of lead compounds, and optimizing new lead molecules. These methods are also effective in recognizing pharma- cophoric units having important interactions with the ligand. Apex-3D, CoMFA, CoMSIA, SoMFA, CoMMA, and AFMoC (Golender and Vorpagel, 1993; Golender and Rosenblit, 1983; Cramer et al., 1988; Klebe et al., 1994; Robinson et al., 1999; Silverman and Platt, 1996) are some of the successful 3D-QSAR methods that have been well explored by the researchers. The most significant among these is the Comparative Molecular Field Analysis (CoM- FA) which was developed by Cramer in 1988. It relies on the principle that there exists a correlation between the fields of interaction surrounding the set of molecules and their displayed biological activity. Comparative Molecular Similarity Indices Analysis (CoMSIA) (Klebe et al., 1994) is another 3D-QSAR technique, which follows the same method of CoMFA but differs in representing the fields. The procedure of CoMFA and CoMSIA involves many steps, of which aligning the molecules is considered to be very important. There are different alignment methods which consider the structure of the ligands alone for aligning the molecules which include fit atom method, flexible align- ment, database alignment and shape-based alignment. Many CoMFA and CoMSIA studies have been reported in the literature based on these two alignments’ approaches (Gohlke and Klebe, 2002; Nayyar et al., 2006; Lemmen et al., 1998; Chakraborti et al., 2003; Akamatsu, 2002; Khanna et al., 2005). Also, techniques such as the ‘‘divide and conquer’’ strategy significantly improved the use and productivity of QSAR methods in the recent years (Aboye et al., 2004; Amin and Welsh, 2001). R. Singh  M. E. Sobhia (&) Centre for Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar, Mohali 160 062, India e-mail: mesophia@niper.ac.in R. Singh e-mail: rajeshsingh2008@gmail.com 123 Med Chem Res (2011) 20:714–725 DOI 10.1007/s00044-010-9365-7 MEDICINAL CHEMISTR Y RESEARCH