Docking & 3D-QSAR Studies of Some Noval Antiproliferative Agents Bull. Korean Chem. Soc. 2013, Vol. 34, No. 3 899 http://dx.doi.org/10.5012/bkcs.2013.34.3.899 Docking, CoMFA and CoMSIA Studies of a Series of N-Benzoylated Phenoxazines and Phenothiazines Derivatives as Antiproliferative Agents Jahan B. Ghasemi, * Elham Aghaee, and Ali Jabbari Chemistry Department, Faculty of Sciences, K. N. Toosi University of Technology, Tehran, Iran * E-mail: Jahan.ghasemi@gmail.com Received October 15, 2012, Accepted December 26, 2012 Using generated conformations from docking analysis by Gold algorithm, some 3D-QSAR models; CoMFA and CoMSIA have been created on 39 N-benzoylated phenoxazines and phenothiazines, including their S- oxidized analogues. These molecules inhibit the polymerization of tubulin into microtubules and thus they have been studied for the development of antitumor drugs. Training set for the CoMFA and CoMSIA models using 30 docked conformations gives q 2 Leave one out (LOO) values of 0.756 and 0.617, and r 2 ncv values of 0.988 and 0.956, respectively. The ability of prediction and robustness of the models were evaluated by test set, cross validation (leave-one-out and leave-ten-out), bootstrapping, and progressive scrambling approaches. The all- orientation search (AOS) was used to achieve the best orientation to minimize the effect of initial orientation of the structures. The docking results confirmed CoMFA and CoMSIA contour maps. The docking and 3D- QSAR studies were thoroughly interpreted and discussed and confirmed the experimental pIC 50 values. Key Words : Phenoxazines and phenothiazines derivatives, Tubulin, CoMFA, CoMSIA, Docking Introduction Microtubules are long, hollow cylindrical biopolymers that are composed of subunits made from a globular cytoplasmic protein known as tubulin, as illustrated in Figure 1. Each subunit of the microtubule is made of two slightly different but closely related simpler units called α-tubulin and β- tubulin that are bound very tightly together to form hetero- dimers. These rope-like polymers of tubulin play an important role in the migration of chromosomes to opposite ends of a mitosing cell during the anaphase. Microtubules are one of the most successful cancer chemotherapeutic targets since they are responsible for mitotic spindle formation and proper chromosomal separation. 1-4 Various drugs have been shown to bind specifically to tubulin in the mitotic spindle and prevent polymerization into the microtubules. Thus these drugs inhibit cell mitosis and lead to cell death. 5-7 Colchicine is one of the most effective inhibitors of tubulin polymeri- zation, 8 however, because of its narrow therapeutic window, colchicine has not found broad application in anticancer therapy. Therefore, there is an urgent need to design and develop new antimitotic agents. The promising usage of micro- tubule-binding drugs for anticancer therapy created great interest in designing microtubule-targeted drugs so great efforts have recently been made to design novel small- molecular tubulin binders. 9-11 Quantitative structure-activity relationship (QSAR) studies perform a vital role in drug discovery and drug design as ligand-based approaches. One would say that today no drug is developed without previous QSAR analyses. The primary aim of QSAR methods is to correlate struc- tural descriptors with biological properties, but it can also be applied to predict the activity value of non-synthesized compounds structurally related to the training sets and helps to clarify the possible molecular mechanism of the receptor- ligand interactions. 12-16 Three-dimensional quantitative structure-activity relation- ship (3D-QSAR) analysis is a common method used in computer-assisted molecular design. Among the 3D-QSAR methods, the comparative molecular field analysis (CoMFA), proposed by Cramer and co-workers, is extensively used in the current practice of drug discovery which it provides the visual display of electrostatic (Coulomb) and steric (Lennard- Jones) fields of the regions important for biological activity. 17 In a similar method, comparative molecular similarity indices analysis (CoMSIA), a probe atom is used to calculate simi- larity indices, at regularly spaced grid points for the aligned molecules. CoMSIA differs from CoMFA, initially in the way that the molecular fields are calculated, which uses a Gaussian-type distance-dependent function to assess five fields of different physicochemical properties (i.e., steric, electrostatic, hydrophobic, and hydrogen bonding donor and acceptor). 18,19 In computational drug design, molecular dock- Figure 1. Structure of microtubule as a target of various anticancer drugs.