Ganguly and Debnath, Med chem 2014, 4:8 DOI: 10.4172/2161-0444.1000194 Research Article Open Access Med chem ISSN: 2161-0444 Med chem, an open access journal Volume 4(8): 558-568 (2014) - 558 Molecular Docking Studies and ADME Prediction of Novel Isatin Analogs with Potent Anti-EGFR Activity Swastika Ganguly* and Biplab Debnath Department of Pharmaceutical Science and Technology, Birla Institute of Technology, Ranchi, India *Corresponding author: Swastika Ganguly, Associate Professor, Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Ranchi, India, Tel: 09431327042; E-mail: swastikaganguly@bitmesra.ac.in Received May 24, 2014; Accepted July 25, 2014; Published July 28, 2014 Citation: Ganguly S, Debnath B (2014) Molecular Docking Studies and ADME Prediction of Novel Isatin Analogs with Potent Anti-EGFR Activity. Med chem 4: 558-568. doi:10.4172/2161-0444.1000194 Copyright: © 2014 Ganguly S, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Keywords: Cancer; Isatin; Epidermal growth factor receptor (EGFR); Tyrosine kinase (TK); Docking; ADME Introduction Cancer is defined as a group of diseases characterized by uncontrolled growth, and the spread of abnormal cells which if leſt untreated may lead to death [1]. Cancer continues to be a major health problem worldwide and more than ten million new cancer cases occur annually, roughly half of which is prevalent in the developed countries, and the disease causes over six million deaths a year [2]. Till date chemotherapy has been the mainstay of cancer therapy. However the use of available chemotherapeutics is oſten limited mainly due to undesirable side effects which include bone marrow depression, alopecia, drug-induced cancer, hepatotoxicity, along with a limited choice of available anti-cancer drugs [3]. Angiogenesis involves the proliferation of endothelial cells (ECs) in response to specific growth stimuli such as vascular endothelial growth factor (VEGF) of basic fibroblast growth factor (bFGF). Each step of the process is controlled by these regulatory growth factors that stimulate or inhibit angiogenesis. However, these control mechanisms are oſten disordered in several pathologic diseases including cancer. e growth and maintenance of solid tumors are highly dependent on neovascularization and can be regulated by compounds that interfere with either the stimulation or proliferation of ECs [4]. Angiogenesis has been intensely investigated as an attractive cancer therapeutic target during the last decade as angiogenesis is the first rate-limiting step for tumor cells to metastasize and is also essential for cancer growth [1]. Some important receptors involved in angiogenesis have been identified, including vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR), and several others. ese growth factor receptor kinases play important roles in the development, progression, aggressiveness, and metastasis of many solid tumors, such as non small cell lung cancer (NSCLC) , head and neck cancers, and glioblastomas. Particularly, the involvement of the EGFR family of tyrosine kinases in cancer proliferation suggests that an inhibitor which blocks the tyrosine kinase activity of the entire EGFR family could have significant therapeutic potential [5]. It is a transmembrane receptor protein comprising of four homologs i. e. EGFR/ErbB1/HER1, HER2/ Neu/ErbB2, HER3/ErbB3 and HER4/ ErbB4. e isatin pharmacophore has attracted, and still attracts, much attention from medicinal chemists because of its structural resemblance to various moieties present in vitamins, proteins and nucleic acids. Isatin moieties are of great importance in their biological as well as synthetic approach of medicinal chemistry. From worldwide reported literature, the various derivatives of isatin are known to possess a range of biological properties including antibacterial and antifungal [6-10], antiviral [11-13], anti-HIV [14,15], antiglycation [16], anticonvulsant and sedative-hypnotic [17,18], anti-inflammatory [19] activities. Various isatin derivatives have been reported to possess cytotoxic activity [20-23]. us isatin is a biologically validated starting point for the design and synthesis of chemical libraries directed at these targets [24]. In recent years, rational drug design has become prevalent widely in the pharmaceutical industry. is involves the use of computational methods which are simple, non-expensive and speed up the process of designing novel and potent molecules with desired biological activity. Docking is a rational approach to drug design which seeks to predict the structure and binding free energy of a ligand-receptor complex given only the structures of the free ligand and receptor [25]. e setup for a ligand docking approach requires the following components: A target protein structure with or without a bound ligand, the molecules of interest or a database containing existing or virtual compounds for the docking process, and a computational framework that allows the implementation of the desired docking and scoring procedures. Docking accuracy reflects an algorithm’s ability to discover a conformation (pose) (http://poseview. zbh. uni-hamburg. de) and alignment of a ligand relative to a cognate protein that is close to that experimentally observed and to recognize the pose as correct. Scoring is the identification of the correct binding pose by its lowest energy value, and the ranking of protein-ligand complexes according to their binding affinities [26]. Molecular docking is oſten used in virtual screening methods [27] whereby large virtual libraries of compounds Abstract Molecular docking studies were performed on 144 newly designed isatin analogs by using Glide v 5. 0 on the active site of five crystal structures of EGFR enzymes (PDB ID 2J5F, 2ITW, 2ITY , 2ITX and1M17) to study the binding mode of these analogs. Binding mode analysis of the compounds with the highest docking scores (-8. 31, -5. 90, -7. 16, -6. 395 and -8. 14) was carried out and were compared with that of the co crystallized ligands DJK_3021_A, AFN 941 , irressa, AMP-PNP and AQ4 in the active sites of 2J5F, 2ITW, 2ITY, 2ITX and 1M17 respectively. ADME properties of all the newly designed isatin analogs 1-144 was calculated by Qik Prop v3. 0. All the designed compounds were found to exhibit lead like properties from the calculated ADME properties. M e d i c i n a l c h e m i s t r y ISSN: 2161-0444 Medicinal chemistry