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Medicinal Chemistry
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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: [email protected]

Received date: May 24, 2014; Accepted date: July 25, 2014; Published date: 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.

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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, AFN941, 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.

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 left 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 chemotherapeuticsis often 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 often disordered in several pathologic diseases including cancer. The 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. These 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.

The 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]. Thus 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. This 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]. The 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 often used in virtual screening methods [27] whereby large virtual libraries of compounds are reduced in size to a manageable subset, which, if successful, includes molecules with high binding affinities to a target receptor.

Previously, synthesis, cytotoxicity and docking studies of hydrazones and Schiff bases of isatin on the target VEGFR-2 have been reported [28]. In the present communication, we wish to report the docking studies of newly designed isatin analogs in to the active site of different crystal structures of the epidermal growth factor receptor (EGFR) kinase domain in complex (PDB ID 1M17, 2J5F , 2ITX, 2ITW and 2ITY respectively) by Glide v5. 0. The results from this study will be useful in understanding the essential pharmacophoric features required for the further development of isatins as anticancer agents.

Materials and Methods

Computational methods by Glide 5. 0

Docking study was performed for all the designed compounds 1–144 by Glide v5. 0 [29] installed in a single machine running on a 3. 4 GHz Pentium 4 processor with 1 GB RAM and 160 GB Hard Disk with Red Hat Linux Enterprise version 5. 0 as the operating system.

Protein structure preparation

The X-ray crystallographic structures of the EGFR proteins (PDB entry code 2J5F, 1M17, 2ITW, 2ITX and 2ITY) were obtained from Brookhaven Protein Data Bank (RCSB) [29,30]. The proteins were prepared using the Protein Preparation Wizard. Preprocessed bond orders were assigned, hydrogens were added, metals were treated, and water molecules were deleted. Energy was minimized (Impref minimization) using RMSD 0. 30 °A. The 3D diagrams of the ligands were drawn by using Maestro 8. 5 implemented in Schrödinger’s suite. The ligands were then prepared and minimized by means of the OPLS_2005 force field [31,32] and the partial atomic charges were computed using the same. The ligand-docking was performed with Glide module in Schrodinger. The XP (Extra Precision) protocol implemented in Glide was employed for the docking studies.

Ligand structure preparation

All the compounds used in the docking study with Glide were built within maestro by using build module of Schrodinger Inc. These structures were geometry optimized by means of the Optimized Potentials for Liquid Simulations-2005 (OPLS 2005) force field with the steepest descent followed by truncated Newton conjugate gradient protocol. Partial atomic charges were computed using the OPLS_2005 force field.

Validation of docking protocol

The most suitable method of evaluating the accuracy of a docking procedure is to determine how intimately the lowest energy pose predicted by the scoring function resembles an experimental binding mode as determined by X-ray crystallography. In the present study, extra precision Glide docking procedure was validated by removing AQ4 (Erlotinib), DJK_3021_A , AMP-PNP, AFN941, Iressa from the binding site and re-docking it to the EGFR proteins (PDB ID:1M17, 2J5F, 2ITX, 2ITW and 2ITY ). We found a very good agreement between the localization of the inhibitors upon docking and from the crystal structures. The root mean square deviations (RMSD) between the predicted conformation and the observed X-raycrystallographic conformation ofcompound AQ4(Erlotinib), DJK_3021_A, AMP-PNP, AFN941, Irressa equaled 1. 737A°, 1. 005A°, 2. 744A°, 2. 931A°, 2. 412A°. This indicates the reliability of the docking methodin reproducing the experimentally observed binding mode for 1M17, 2J5F, 2ITX, 2ITW and 2ITY.

Docking and scoring function

All the conformers from the confgen-ligprep output were docked in the EGFR tyrosine kinase active site. All default parameters were used for extra precision docking. Glide extra precision mode was employed for the current docking study. Best poses were chosen for energy minimization during docking, a distance dependent dielectric constant of 2. 0 and maximum number of minimization step of 100 was used. The docking simulations (ligand receptor interactions) are scored using the Extra Precision (XP) mode which is implemented in GLIDE v5. 0.

Finally, the minimized poses were rescored using Schrodinger’s proprietary GlideScore scoring function.

In this docking method, the ligands are flexible and receptor is rigid except that the protein active site which has slight flexibility. To include receptor flexibility the ligands were docked into different grids generated for five protein conformations [33,34].

ADME prediction

ADME properties were calculated using Qikprop v3. 0 tool of Schrodinger software. It predicts both physicochemically significant descriptors and pharmacokinetically significant properties. QikProp provides ranges for comparing a exacting molecule’s properties with those of 95% of known drugs. QikProp also flags 30 types of reactive functional groups that may cause false positives in hight throughput screening (HTS) assays. It also evaluates the suitability of analogs based on Lipinski’s rule of five [35], which is essential to ensure druglike pharmacokinetic profile while using rational drug design. All the analogs were neutralized before being used by Qikprop.

Results

Docking studies

A large number of EGFR crystal structures have been reported in the literature which have different conformations. In this work we have considered five crystal structures (PDB ID:1M17, 2J5F, 2ITX, 2ITW and 2ITY ) that are co-crystallized with inhibitors AQ4 (Erlotinib), DJK_3021_A , AMP-PNP, AFN941, Irressa respectively. Docking studies were performed using Glide v5. 0 on five high resolution crystal structures of EGFR enzyme to study the binding modes of quality and quantum interactions between differently substituted newly designed isatin analogs (Table 1) with the enzyme epidermal growth factor receptor (EGFR) kinase domain in complex (PDB ID 1M17, 2J5F, 2ITX , 2ITW and 2ITY) results of which are depicted in Table 2.

image
Comp.  Code R1 R2 Comp. Code R1 R2
1 -H -H 46 -4-Cl 2,5-CH3
2 -H -2-Cl 47 -4-Cl 3,4-CH3
3 -H -3-Cl 48 -4-Cl 2-NO2
4 -H -4-Cl 49 -2-CH3 -H
5 -H -2-CH3 50 -2-CH3 -2-Cl
6 -H -4-CH3 51 -2-CH3 -3-Cl
7 -H 3-OCH3 52 -2-CH3 -4-Cl
8 -H 4-OCH3 53 -2-CH3 -2-CH3
9 -H 2,4-CH3 54 -2-CH3 -4-CH3
10 -H 2,5-CH3 55 -2-CH3 3-OCH3
11 -H 3,4-CH3 56 -2-CH3 4-OCH3
12 -H 2-NO2 57 -2-CH3 2,4-CH3
13 -2-Cl -H 58 -2-CH3 2,5-CH3
14 -2-Cl -2-Cl 59 -2-CH3 3,4-CH3
15 -2-Cl -3-Cl 60 -2-CH3 2-NO2
16 -2-Cl -4-Cl 61 -4-CH3 -H
17 -2-Cl -2-CH3 62 -4-CH3 -2-Cl
18 -2-Cl -4-CH3 63 -4-CH3 -3-Cl
19 -2-Cl 3-OCH3 64 -4-CH3 -4-Cl
20 -2-Cl 4-OCH3 65 -4-CH3 -2-CH3
21 -2-Cl 2,4-CH3 66 -4-CH3 -4-CH3
22 -2-Cl 2,5-CH3 67 -4-CH3 3-OCH3
23 -2-Cl 3,4-CH3 68 -4-CH3 4-OCH3
24 -2-Cl 2-NO2 69 -4-CH3 2,4-CH3
25 -3-Cl -H 70 -4-CH3 2,5-CH3
26 -3-Cl -2-Cl 71 -4-CH3 3,4-CH3
27 -3-Cl -3-Cl 72 -4-CH3 2-NO2
28 -3-Cl -4-Cl 73 3-OCH3 -H
29 -3-Cl -2-CH3 74 3-OCH3 -2-Cl
30 -3-Cl -4-CH3 75 3-OCH3 -3-Cl
31 -3-Cl 3-OCH3 76 3-OCH3 -4-Cl
32 -3-Cl 4-OCH3 77 3-OCH3 -2-CH3
33 -3-Cl 2,4-CH3 78 3-OCH3 -4-CH3
34 -3-Cl 2,5-CH3 79 3-OCH3 3-OCH3
35 -3-Cl 3,4-CH3 80 3-OCH3 4-OCH3
36 -3-Cl 2-NO2 81 3-OCH3 2,4-CH3
37 -4-Cl -H 82 3-OCH3 2,5-CH3
38 -4-Cl -2-Cl 83 3-OCH3 3,4-CH3
39 -4-Cl -3-Cl 84 3-OCH3 2-NO2
40 -4-Cl -4-Cl 85 4-OCH3 -H
41 -4-Cl -2-CH3 86 4-OCH3 -2-Cl
42 -4-Cl -4-CH3 87 4-OCH3 -3-Cl
43 -4-Cl 3-OCH3 88 4-OCH3 -4-Cl
44 -4-Cl 4-OCH3 89 4-OCH3 -2-CH3
45 -4-Cl 2,4-CH3 90 4-OCH3 -4-CH3
91 4-OCH3 3-OCH3 118 2,5-CH3 2,5-CH3
92 4-OCH3 4-OCH3 119 2,5-CH3 3,4-CH3
93 4-OCH3 2,4-CH3 120 2,5-CH3 2-NO2
94 4-OCH3 2,5-CH3 121 3,4-CH3 -H
95 4-OCH3 3,4-CH3 122 3,4-CH3 -2-Cl
96 4-OCH3 2-NO2 123 3,4-CH3 -3-Cl
97 2,4-CH3 -H 124 3,4-CH3 -4-Cl
98 2,4-CH3 -2-Cl 125 3,4-CH3 -2-CH3
99 2,4-CH3 -3-Cl 126 3,4-CH3 -4-CH3
100 2,4-CH3 -4-Cl 127 3,4-CH3 3-OCH3
101 2,4-CH3 -2-CH3 128 3,4-CH3 4-OCH3
102 2,4-CH3 -4-CH3 129 3,4-CH3 2,4-CH3
103 2,4-CH3 3-OCH3 130 3,4-CH3 2,5-CH3
104 2,4-CH3 4-OCH3 131 3,4-CH3 3,4-CH3
105 2,4-CH3 2,4-CH3 32 3,4-CH3 2-NO2
106 2,4-CH3 2,5-CH3 133 2-NO2 -H
107 2,4-CH3 3,4-CH3 134 2-NO2 -2-Cl
108 2,4-CH3 2-NO2 135 2-NO2 -3-Cl
109 2,5-CH3 -H 136 2-NO2 -4-Cl
110 2,5-CH3 -2-Cl 137 2-NO2 -2-CH3
111 2,5-CH3 -3-Cl 138 2-NO2 -4-CH3
112 2,5-CH3 -4-Cl 139 2-NO2 3-OCH3
113 2,5-CH3 -2-CH3 140 2-NO2 4-OCH3
114 2,5-CH3 -4-CH3 141 2-NO2 2,4-CH3
115 2,5-CH3 3-OCH3 142 2-NO2 2,5-CH3
116 2,5-CH3 4-OCH3 143 2-NO2 3,4-CH3
117 2,5-CH3 2,4-CH3 144 2-NO2 2-NO2

Table 1: Structures of newly designed isatin analogs 1-144.

Compound Combined (Gscore) 1M17(Gscore) 2J5F(Gscore) 2ITW(Gscore) 2ITX (Gscore) 2ITY (Gscore)
Ref -35.9 -8.74 -7.68 -5.73 -9.1 -4.65
143 -32.29 -8.10 -5.88 -5.66 -4.98 -7.67
84 -29.03 -6.89 -8.21 -4.52 -5.04 -4.37
120 -28.88 -8.09 -5.91 -4.98 -4.76 -5.14
24 -28.55 -5.79 -6.66 -5.52 -4.44 -6.14
139 -28.5 -5.43 -7.26 -5.07 -3.33 -7.41
12 -28.18 -5.65 -8.31 -4.33 -4.57 -5.32
108 -28.1 -8.14 -5.62 -4.51 -4.92 -4.91
80 -28.09 -5.2 -5.75 -5.33 -6.395 -5.46
62 -28.08 -7.6 -6.26 -4.87 -5.18 -4.17
125 -27.89 -7.58 -6.25 -5.01 -5.09 -3.96
144 -27.89 -5.15 -6.45 -4.72 -4.69 -6.88
55 -27.38 -6.24 -5.52 -5.42 -4.51 -5.69
137 -27.37 -4.17 -7.65 -4.34 -4.32 -6.89
106 -27.31 -7.1 -6.51 -4.37 -4.29 -5.04
73 -27.25 -5.79 -5.65 -5.19 -5.67 -4.95
19 -27.13 -6.48 -5.22 -5.26 -5.23 -4.94
142 -27.90 -8.05 -4.49 -4.68 -4.88 -4.99
79 -27.08 -5.9 -4.4 -4.37 -6.23 -6.18
132 -27.01 -6.1 -6.3 -4.78 -4.61 -5.22
82 -26.99 -5.8 -5.8 -3.76 -5.72 -5.91
96 -26.85 -5.93 -6.07 -4.21 -5.8 -4.84
48 -26.85 -5.9 -6.25 -4.5 -5.57 -4.63
95 -26.75 -5.84 -6.06 -3.88 -5.78 -5.19
N85 -26.72 -5.81 -6.06 -4.29 -5.9 -4.66
41 -26.68 -6.03 -6.23 -4.04 -5.48 -4.9
75 -26.57 -6.25 -6.13 -3.78 -6.03 -4.38
77 -26.57 -5.85 -5.85 -4.18 -5.92 -4.77
127 -26.56 -5.95 -6.25 -4.64 -4.09 -5.63
32 -26.44 -5.83 -4.41 -5.05 -5.92 -5.23
60 -26.42 -5.45 -6.24 -4.66 -5.33 -4.74
20 -26.4 -5.63 -5.53 -5.24 -5.5 -4.5
29 -26.34 -7.3 -5.86 -4.33 -3.71 -5.14
8 -26.34 -5.68 -5.81 -5.01 -4.55 -5.29
91 -26.14 -6.3 -5.88 -4.93 -4.11 -4.92
130 -26.14 -6.17 -6.54 -3.51 -4.88 -5.04
40 -26.12 -6.16 -6.31 -3.31 -5.51 -4.83
123 -26.08 -6.4 -6.24 -4.52 -3.55 -5.37
83 -26.06 -6.45 -5.43 -4.49 -4.62 -5.07
N46 -26.01 -6.24 -5.96 -4.45 -4.46 -4.9
N38 -26 -6.48 -6.24 -4.12 -4.56 -4.6
68 -25.94 -5.94 -5.68 -5.91 -4.1 -4.31
141 -25.91 -8.37 -5.79 -4.01 -5.09 -2.65
36 -25.87 -6.03 -5.69 -3.82 -5.67 -4.66
140 -25.87 -8.21 -5.41 -5.7 -3.67 -2.88
2 -25.86 -5.86 -5.99 -4.64 -3.79 -5.58
121 -25.75 -6.63 -4.14 -5.05 -4.62 -5.31
11 -25.69 -5.75 -5.29 -5.05 -4.56 -5.04
78 -25.66 -5.97 -4.78 -4.59 -5.74 -4.58
5 -25.65 -6.07 -5.8 -3.99 -5.13 -4.66
76 -25.61 -5.74 -5.84 -3.99 -5.08 -4.96
138 -25.59 -4.89 -4.58 -4.4 -4.32 -7.4
44 -25.57 -5.94 -4.56 -4.8 -5.96 -4.31
56 -25.52 -6.1 -5.38 -5.45 -4.35 -4.24
14 -25.49 -5.64 -5.26 -4.55 -4.76 -5.28
3 -25.4 -6.07 -5.92 -4.46 -4.54 -4.41
70 -25.36 -5.61 -6.03 -3.95 -5.21 -4.56
115 -25.18 -6.32 -3.58 -4.4 -5.69 -5.19
97 -25.16 -5.54 -5.47 -4.88 -3.78 -5.49
98 -25.15 -5.54 -6.47 -4.63 -4.02 -4.49
74 -25.02 -6.13 -5.57 -3.71 -4.96 -4.65
1 -25.02 -5.59 -5.77 -4.52 -4.84 -4.3
45 -24.96 -5.9 -6.22 -4.46 -3.59 -4.79
61 -24.95 -6.28 -6.42 -4.58 -3.44 -4.23
10 -24.92 -5.45 -4.67 -4.21 -5.26 -5.33
39 -24.91 -5.61 -6.04 -3.89 -5.64 -3.73
28 -24.82 -5.79 -4.18 -4.83 -4.92 -5.1
16 -24.81 -5.58 -5.39 -4.86 -4.92 -4.06
72 -24.8 -5.06 -4.96 -4.73 -5.77 -4.28
27 -24.8 -6.19 -5.56 -4.84 -3.4 -4.81
9 -24.79 -5.94 -5.12 -4.61 -4.98 -4.14
87 -24.79 -5.53 -4.51 -4.01 -5.71 -5.03
53 -24.73 -5.43 -6.03 -4.43 -3.94 -4.9
124 -24.72 -4.31 -6.43 -3.27 -5.38 -5.33
47 -24.71 -3.46 -6.12 -4.28 -5.58 -5.27
103 -24.65 -6.08 -6.17 -3.03 -4.08 -5.29
111 -24.49 -5.54 -4.33 -5.08 -5.09 -4.45
22 -24.47 -6.21 -3.82 -4.44 -4.95 -5.05
23 -24.44 -5.31 -4.47 -4.61 -4.74 -5.31
135 -24.34 -5.03 -4.66 -4.85 -4.79 -5.01
4 -24.3 -5.81 -5.78 -4.06 -4.22 -4.43
86 -24.27 -3.15 -6.3 -4.81 -4.64 -5.37
21 -24.14 -4.81 -5.15 -4.26 -4.6 -5.32
31 -24.1 -6.26 -3.64 -4.36 -4.24 -5.6
7 -24.09 -2.75 -5.55 -5.41 -4.78 -5.6
65 -24.04 -7.19 -6.27 -4.04 -2.22 -4.32
49 -24.01 -4.85 -5.14 -4.53 -4.58 -4.91
101 -23.97 -5.76 -4.16 -4.22 -4.62 -5.21
112 -23.96 -5.53 -4.46 -4.51 -4.55 -4.91
51 -23.95 -5.45 -4.5 -5.09 -4.23 -4.68
50 -23.94 -3.99 -5.83 -4.52 -4.76 -4.84
67 -23.83 -4.38 -4.97 -4.82 -4.31 -5.35
90 -23.8 -4.95 -4.69 -3.87 -5.56 -4.73
107 -23.74 -4.72 -4.06 -4.48 -4.7 -5.78
25 -23.59 -5.79 -4.75 -4.12 -3.9 -5.03
58 -23.59 -4.86 -5.56 -4.05 -4.28 -4.84
92 -23.57 -3.1 -5.01 -4.89 -6.34 -4.23
89 -23.49 -6.12 -4.3 -4.15 -3.81 -5.11
128 -23.42 -3.05 -6.2 -5.05 -4.86 -4.26
129 -23.38 -3.36 -6.85 -3.9 -4.55 -4.72
35 -23.34 -5.53 -5.87 -4.21 -3.52 -4.21
30 -23.07 -6.19 -4.97 -2.56 -4.93 -4.42
94 -23.02 -7.45 -5.07 -3.73 -2.16 -4.61
119 -22.97 -5.1 -5.93 -3.44 -4.55 -3.95
88 -22.95 -5.63 -5.47 -3.47 -5.01 -3.37
93 -22.93 -5.52 -3.97 -3.73 -5.32 -4.39
102 -22.92 -5.28 -3.96 -4.36 -3.91 -5.41
43 -22.9 -5.71 -4.14 -4.75 -4.5 -3.8
13 -22.82 -5.17 -4.62 -4.78 -4.32 -3.93
116 -22.79 -5.21 -4.62 -4.85 -3.39 -4.72
6 -22.71 -4.43 -5.37 -4.17 -4.25 -4.49
33 -22.62 -3.65 -5.91 -3.67 -5.09 -4.3
134 -22.36 -4.77 -4.05 -4.26 -4.79 -4.49
109 -22.29 -5.67 -4.5 -4.32 -3.54 -4.26
66 -22.26 -6.01 -6.04 -3.56 -4.4 -2.25
131 -22.25 -3.7 -3.89 -4.26 -5.69 -4.71
114 -22.1 -6.12 -3.88 -4.54 -3.54 -4.02
118 -22.04 -5.85 -4.15 -4.48 -3.87 -3.69
126 -21.91 -3.62 -4.41 -3.54 -5.79 -4.55
26 -21.86 -6.27 -5.89 -4.03 -4.05 -1.62
113 -21.74 -4.24 -4.91 -4.27 -3.65 -4.67
37 -21.74 -6.1 -5.03 -3.79 -5.51 -1.31
133 -21.64 -4.59 -4.29 -4.22 -4.71 -3.83
136 -21.62 -6.19 -4.62 -1.42 -4.51 -4.88
15 -21.56 -4.68 -4.08 -4.85 -4.4 -3.55
69 -21.56 -2.73 -4.92 -4.52 -5.14 -4.25
59 -21.32 -1.75 -4.14 -4.34 -5.43 -5.66
63 -21.22 -5.75 -3.69 -3.45 -3.27 -5.06
110 -21.16 -2.95 -4.36 -4.55 -4.95 -4.35
117 -21.14 -3.94 -5.74 -3.21 -3.88 -4.37
17 -21.08 -4.09 -4.46 -4.46 -4.37 -3.7
54 -21 -2.67 -5.38 -4.42 -3.36 -5.17
81 -20.92 -2.85 -4.22 -3.9 -5.18 -4.77
18 -20.86 -3.03 -5.02 -4.61 -4.4 -3.8
34 -20.54 -2.58 -5.5 -3.95 -3.62 -4.89
42 -20.44 -4.07 -5.86 -2.8 -4.49 -3.22
57 -20.43 -4.76 -5.55 -2.14 -3.9 -4.08
99 -20.42 -4.49 -3.9 -4.01 -3.89 -4.13
105 -20.18 -5.12 -5.87 -4.3 -4.2 -0.69
100 -19.98 -5.53 -4.25 -1.12 -3.45 -5.63
64 -18.83 -3.52 -3.95 -3.85 -3.53 -3.98
104 -18.58 -3.21 -4.07 -4.98 -3.8 -2.52
71 -17.71 -2.41 -6.25 -3.85 -3.2 -2
52 -17.21 -4.21 -5.4 -3.35 -2.01 -2.24
122 -15.79 -5.06 -6.18 -4.96 -4.38 4.79

Table 2: Results of molecular docking studies of compounds 1-144 in the active sites of EGFR proteins (PDB ID1M17,2J5F,2ITW,2ITX and 2ITY) performed using extra precision mode of Glide.

Docking studies were performed using Glide v5. 0 in the active sites of five high resolution crystal structures of EGFR enzyme in order to investigate the possible interactions between the designed isatin analogs and the active site of the epidermal growth factor receptor (EGFR) kinase and were compared with the binding mode of the known EGFR inhibitors EGFRTK- Erlotinib complex or [6, 7-bis(2-methoxy-ethoxy)quinazoline-4-yl]-(3-ethynylphenyl) amine (AQ4), N-[4-(3- bromo phenylamino) quinazolin-6-yl] acrylamide (DJK_3021_A) , EGFR inhibitor AFN 941, EGFR inhibitor AMP-PNP and EGFR inhibitor Irressa respectivly. The X-ray structure of the enzymes (PDB ID: 1M17, 2J5F, 2ITW , 2ITX and 2ITY) bounded with AQ4(Erlotinib) , DJK_3021_A, AFN941, AMP-PNP and Irressa was taken from the protein data bank; (http://www. rcsb. org/pdb).

The reliability of the docking results was first checked by comparing the best docking poses obtained for the cocrystallized inhibitor with its bound conformation. This was done by removing each ligand from their active site and subjecting again to redocking into the binding pocket in the conformation found in the crystal structure. As a result, a root mean square deviation (RMSD) of 1.737A°, 1.005A°, 2.744A°, 2. 931A°, 2. 412A° for EGFR proteins PDB ID:1M17, 2J5F, 2ITX, 2ITW and 2ITY cocrystalized with. Erolotinib, DJK, AFN 941, AMP-PNP and Irressa respectively were found suggesting that the docking procedure could be relied onto predict the binding mode of our compounds.

The X-ray structure of the enzyme cocrystallized with DJK_3021_A was taken from the proteindata bank; PDB ID 2J5F [25]. The EGFR tyrosine kinase binding site contains the important residues Thr 790, Met 793, Lys 745, Met 766, Cys797 , Ala 743 and Leu788. The three dimensional docked pose of DJK_3021_A and the compound 12 in the active site of 2J5F has been depicted in Figure 1a and Figure 2a while the residues involved in inter-atomic contact has been shown in the schematic 2D representation as in Figure 1b and Figure 2b respectively. The binding mode analysis revealed that the the isatin scaffold in compound 12 is oriented in the binding site similarly as the quinazoline moiety of the cocrystallized ligand DJK_3021_A. The isatin scaffold is favorably embedded in the hydrophobic pocket surrounded by the side chains of Leu 718, Lys745 and Phe723. The compound also shows one H-bond interaction between the hydrophilic spacer group CH2-CONH and the hydroxyl group present in residue ASP 855 (NHCH3CHCONH ___OH ASP855 =1. 643 A°). These interactions may be responsible for the binding affinity of the molecule as indicated by the docking scores −8. 31 comparable and more than the docking score -7. 68 of the reference ligand DJK_3021_A.

medicinal-chemistry-Redocked-conformer

Figure 1(a). Redocked conformer of ligand DJK_3021_A in the active site of the protein EGFR (PDB ID 2J5F). 1(b). 2D representation of ligand DJK_3021_A. 2(a). Active site of the protein EGFR (PDB ID 2J5F) – molecular model compound 12. 2(b). Schematic 2D representation of interaction of compound 12 in the binding pocket of the protein. Active site amino acid residues are represented as tubes, while the inhibitor is shown as ball and stick model with the atoms colored as carbon: green, nitrogen: blue, oxygen: red. Hydrogen bond interactions are represented by yellow dotted lines. Pose view: black dashed lines - hydrogen bonds, salt bridges, metal interactions; green solid lines - hydrophobic interactions; green dashed lines - Pi-Pi, Pi-cation interaction.

The 2ITW X ray crystal structure is co-crystallized with the ligand Staurosporine which has multiple ring structures and therefore is mostly stabilized by the hydrophobic interactions contributed by Leu718, Leu792, Leu844 and Lys745 while hydrogen bonds are present between the receptor residues Met793 and the ligand Staurosporine which is displayed in Figure 3a and 3b [36]. The docking pose of compound 68 in the active site of 2ITW has been represented in its three dimensional mode in Figure 4a while the schematic 2D dimensional representation has been shown in Figure 4b. The docking pose analysis revealed that the isatin scaffold is oriented in the hydrophobic pocket surrounded by the side chains of Leu 718, Leu 844 , Lys745 and Asp 745 in the active site of the EGFR protein 2ITW. The compound also shows three H-bond interactions, one being between NH group of the -CH2CONH and the C=O group present in residue Met 793 (NHCH2CONH ___C=O Met793 =1. 889 A°), a second H-bond between C=O group of isatin and NH group present in residue Met 793 (C=O isatin ring ___NH Met793 =2. 041phenyl ring ___NH Lys716 =2. 148 A°)). These interactions increase the binding affinity of the molecule as indicated by the docking score of the compound 68 as −5. 90 comparable and slightly more than the dock score -5. 735 of the reference ligand Staurosporine.

medicinal-chemistry-hydrophobic-interactions

Figure 3(a). Redocked conformer of ligand AFN941 in active site of the protein EGFR (PDB ID 2ITW). 3(b). 2D representation of ligand AFN941. 4(a). Active site of the protein EGFR (PDB ID 2ITW) of molecular model compound 68. 4(b). Schematic 2D representation of interactions of protein EGFR with compound 68in binding pocket. Active site amino acid residues are represented as tubes, while the inhibitor is shown as ball and stick model with the atoms colored as carbon: green, nitrogen: blue, oxygen: red. Hydrogen bond interactions are represented by yellow dotted lines. Pose view: black dashed lines - hydrogen bonds, salt bridges, metal interactions; green solid lines - hydrophobic interactions; green dashed lines - Pi-Pi, Pi-cation interaction.

The next EGFR protein (PDB ID 2ITY) cocrystallized with the ligand iressa shows only one H-bond between the amide nitrogen of Met793 and the ligand as depicted in Figure 5a and 5b. In this case, the compound 79 , showed the highest docking score (−7. 16 ) in the active site of 2ITY [25]. In fact the dock score was higher than that of the cocrystallized ligand iressa (-4. 65). The three dimensional representation of the docked pose of compound 79 has been shown in Figure 6a and the residues involved in inter-atomic contact has been shown in Figure 6b. The docking pose study of compound 79 revealed that the isatin scaffold is oriented in the binding site similarly as in case of the cocrystallized ligand Iressa in the active site of 2ITY. As in the previous cases, the isatin scaffold is oriented in the hydrophobic pocket surrounded by the side chains of Leu 844, Leu 718, Pro794, Lys745 and Phe723. The compound also shows two H-bond interactions between the NH group of the -CH2CONH and the hydroxyl group present in residue ASP 855 (NHCH3CHCONH ___OH =1. 855 A°) and between the methoxy group substituted at the meta position of the phenyl ring and NH goup present in residue Met 793 (OCH3 Phenyl ring ___NH Met79=1. 729 A°) respectively. These interactions and hydrogen bonding may increase the binding affinity of the molecule significantly as indicated by a very high docking score of of the compound 79 as compared to that of the cocrystallized ligand Irressa.

medicinal-chemistry-atoms-colored-carbon

Figure 5(a). Redocked conformer of ligand irressa in active site of the protein EGFR (PDB ID 2ITY). 5(b). 2D representation of ligand irreessa. 6(a). Active site of the protein EGFR (PDB ID 2ITY) of molecular model compound 79. 6(b). Schematic 2D representation of interactions of compound 79 with protein EGFR in binding pocket. Active site amino acid residues are represented as tubes, while the inhibitor is shown as ball and stick model with the atoms colored as carbon: green, hydrogen: cyan, nitrogen: blue, oxygen: red. Hydrogen bond interactions are represented by yellow dotted lines.Pose view: black dashed lines - hydrogen bonds, salt bridges, metal interactions; green solid lines - hydrophobic interactions; green dashed lines - Pi-Pi, Pi-cation interaction.

Further, the next EGFR protein (PDB ID 2ITX) co-crystallized with the ligand AMP-PNP also shows H-bond interactions present between the receptor residues (Met793 and Asp855) and the cocrystallized ligand AMP-PNP as represented in Figure 7a and 7b [25]. Among all the novel designed isatin analogs, compound 80 with the highest docking score in the active site of 2ITX is visualized in its three dimensional mode in Figure 8a and the residues involved in inter-atomic contact has been shown in Figure 8b. The docking pose visualization revealed that in compound 80 the isatin scaffold is oriented in the binding site similarly as the cocrystallized ligand AMP-PNP in the active site of 2ITX and is favorably embedded in the hydrophobic pocket surrounded by the side chains of Leu 844, Leu 718, Pro794, Lys745 and Phe723. The compound also shows two H-bond interactions, one between the NH group of the -CH2CONH and the C=O group present in residue Pro794 (NHCH2CONH__CO Pro794=2. 138 A°) and the second being between the C=O group present in the isatin moiety linkage with NH group present in Met 793 residue (CO isatin ring___NH Met793=2. 038 A°). However, the docking score of compound 80 (-6. 395) was less than that of the cocrystallized ligand AMP-PNP(-9. 101).

medicinal-chemistry-hydrogen-bonds-salt-bridges

Figure 7(a). Redocked conformer of ligand AMP-PNP in active site of protein EGFR (PDB ID 2ITX). 7(b) 2D representation of ligand AMP-PNP. 8(a). Active site of the protein EGFR (PDB ID 2ITX) with Molecular model compound 80.8(b).Schematic 2D representation of interaction of compound 80 with protein EGFR in the binding pocket. Active site amino acid residues are represented as tubes, while the inhibitor is shown as ball and stick model with the atoms colored as carbon: green, hydrogen: cyan, nitrogen: blue, oxygen: red. Hydrogen bond interactions are represented by yellow dotted lines Pose view: black dashed lines - hydrogen bonds, salt bridges, metal interactions; green solid lines - hydrophobic interactions; green dashed lines - Pi-Pi, Pi-cation interaction.

In case of PDB ID 1M17 complexed with the cocrystallized ligand erlotinib(AQ4), the ligand shows H-bond interactions with Met 769 as depicted in Figure 9a and 9b [37]. The interactions with threonine and methionine are very important for stable binding of AQ4 in the active site of 1M17. The three dimensional docked pose of compound 108 in the active site of 1M17 has been depicted in Figure 10a and the residues involved in inter-atomic contact has been shown in the schematic 2D representation as in Figure 10b. The docking pose study revealed that in compound 108 the isatin scaffold is oriented in the binding site likewise as the quinazoline moiety of erlotinib in the active site of 1M17. Here in, the isatin moiety interacts with multiple amino acid residues Met769, Leu820, Leu 764, Ala719, Lys721, Thr 766 , Thr 830 and Gly722. The compound also shows two H-bond interactions between the C=O group of the -CH2CONH and the hydroxyl group present in residue Tyr 830 (COCH3CHCONH ___OH Tyr830=2. 250 A°) while another hydrogen bond interaction was evident between oxygen atom of NO2 group at the para position of phenyl ring and hydrogen atom of NH group of Lys 712 residue (NO2 phenyl ring___NH Lys712=3. 892 A°). These interactions and the hydrogen bonding increases the binding affinity of the molecule as indicated by the docking scores −8.14 which is comparable to the dock score of the refernce ligand -8. 745.

medicinal-chemistry-binding-pocket-Active

Figure 9(a). Redocked conformer of AQ4 in the active site of the protein EGFR (PDB ID 1M17), 9(b) 2D representation of ligand AQ4, 10(a).Active site of the protein EGFR (PDB ID 1M17) with molecular model compound 108 and 10(b). Schematic 2D representation of interaction of compound 108 with protein EGFR in the binding pocket. Active site amino acid residues are represented as tubes, while the inhibitor is shown as ball and stick model with the atoms colored as carbon: green, hydrogen: cyan, nitrogen: blue, oxygen: red. Hydrogen bond interactions are represented by yellow dotted lines Pose view: black dashed lines - hydrogen bonds, salt bridges, metal interactions; green solid lines - hydrophobic interactions; green dashed lines - Pi-Pi, Pi-cation interaction.

ADME properties

We have analyzed 144 physically descriptors and pharmaceutically significant properties of isatin analogs using Qikprop v3. 0 tool of Schrodinger software, among which major descriptors reported here are required for predicting the drug-like properties of molecules. These properties are

1. Molecular weight (mol_MW) (150–650)

2. Octanol/water partition coefficient (Log Po/w) (-2–6. 5)

3. Aqueous solubility (QPlogS) (-6. 5–0. 5)

4. Apparent MDCK cell permeability (QPPMDCK) (<25 poor, >500 great)

5. Brain/blood partition coefficient (QPlogBB)(-3. 0–1. 2)

6. Percent human oral absorption (≥ 80% is high, ≤ 25% is poor)

All the structures showed significant values for the properties analyzed (Table 3) and exhibited drug-like characteristics based on Lipinski’s rule of 5. The ADME values of newly designed compounds 1-144 are given in Table 3. The first three properties are based on Lipinski rule of five, molecular weight (mol_MW) less than 650, partition coefficient between octanol and water (logPo/w) between -2 and 6. 5 and solubility (QPlogS) greater than -7. Brain/blood partition coefficient (QPlogBB) parameter indicated about the ability of the drug to pass through the blood–brain barrier which is mandatory for inhibition of EGFR kinase. The QPPMDCK predicted apparent MDCK cell permeability in nm/s. MDCK cells are considered to be a good mimic for the blood–brain barrier. Higher the value of MDCK cell, higher the cell permeability.

Compound  code Mol..Wt Log Po/w Log S Log BB PMDCK Human oral absorption (%) Rule of five
1 355.395 3.665 -5.066 -0.782 537.838 100 0
2 389.84 4.181 -5.382 -0.433 1529.7 100 0
3 389.84 4.451 -5.995 -0.378 2403 100 0
4 389.84 4.451 -5.992 -0.377 2410.1 100 0
5 369.422 4.115 -5.288 -0.498 1008.6 100 0
6 369.422 4.268 -5.827 -0.558 976.111 100 0
7 385.421 4.047 -5.377 -0.588 1016 100 0
8 385.421 4.036 -5.416 -0.611 976.068 100 0
9 383.449 4.592 -6.218 -0.49 1143.2 100 0
10 383.449 4.591 -6.218 -0.491 1141.5 100 0
11 383.449 4.535 -6.238 -0.0569 973.002 100 0
12 400.393 3.388 -4.758 -1.1 276.456 96.294 0
13 389.84 4.107 -5.607 0.603 1233.9 100 0
14 424.285 4.327 -5.73 -0.494 1930.2 100 0
15 424.285 4.595 -6.349 -0.451 3028.9 100 0
16 424.285 4.597 -6.341 -0.449 3045.7 100 0
17 403.867 4.183 -5.637 -0.56 1272.8 100 0
18 403.867 4.414 -6.178 -0.632 1230.6 100 0
19 419.866 4.565 -5.784 -0.685 1230.9 100 0
20 419.866 4.189 -5.77 -0.684 1230.2 100 0
21 417.894 4.568 -6.196 -0.588 1272.66 100 0
22 417.894 4.683 -6.202 -0.588 1272.4 100 0
23 417.894 4.155 -6.594 -0.647 1226.6 100 0
24 434.838 3.47 -5.663 -1.529 179.204 88.394 0
25 389.84 4.156 -5.8 -0.629 1326.9 100 0
26 424.285 4.375 -5.921 -0.518 2076.2 100 0
27 424.285 4.647 -6.538 -0.476 3266.1 100 0
28 424.285 4.647 -6.535 -0.475 3275.8 100 0
29 403.86 4.236 -5.827 -0.584 1368.3 100 0
30 403.867 4.122 -6.37 -0.658 1326.8 100 0
31 419.866 3.889 -5.959 -0.691 1381.1 100 0
32 419.866 4.784 -5.955 -0.709 1325.6 100 0
33 417.894 4.616 -6.394 -0.613 1368.2 100 0
34 417.894 4.616 -6.394 -0.613 1369.6 100 0
35 417.894 4.731 -6.783 -0.672 1322.4 100 0
36 434.838 3.581 -5.292 -1.184 376.398 93.15 0
37 389.84 4.646 -5.799 -0.628 1327.9 100 0
38 424.285 4.648 -6.353 -0.405 3500.8 100 0
39 424.285 3.581 -6.538 -0.476 3274.1 100 0
40 424.285 4.632 -6.534 -0.475 3277.9 100 0
41 403.867 3.558 -6.531 -0.443 2317.8 100 0
42 403.867 4.552 -6.365 -0.657 1327.9 100 0
43 419.866 4.248 -5.969 -0.696 1382.3 100 0
44 419.866 4.231 -5.956 -0.709 1327.4 100 0
45 417.894 4.787 -6.76 -0.591 1554.5 100 0
46 417.894 4.787 -6.76 -0.592 1552.2 100 0
47 417.894 4.731 -6.782 -0.672 1323.2 100 0
48 434.834 3.581 -5.293 -1.184 376.405 93.147 0
49 369.422 3.959 -6.173 -0.651 1547.9 100 0
50 403.867 4.436 -5.975 -0.507 1618.8 100 0
51 403.867 4.451 -6.161 -0.575 1507.8 100 0
52 403.867 4.45 -6.174 -0.579 174.529 100 0
53 383.449 4.114 -5.45 -0.686 634.361 100 0
54 383.449 4.265 -5.988 -0.756 614.087 100 0
55 399.448 4.053 -5.584 -0.791 639.231 100 0
56 399.448 4.034 -5.579 -0.609 613.9 100 0
57 397.476 3.053 -5.788 -0.525 1552.5 100 0
58 397.476 3.551 -5.629 -0.541 1544.5 100 0
59 397.476 3.148 -5.658 -0.553 1550.5 100 0
60 414.82 3.387 -4.915 -1.278 174.529 92.978 0
61 369.422 3.97 -5.629 -0.811 537.65 100 0
62 403.867 4.19 -5.751 -0.701 841.189 100 0
63 403.867 4.461 -6.367 -0.659 1322.9 100 0
64 403.867 4.461 -6.364 -0.657 1327 100 0
65 383.449 4.124 -5.658 -0.766 554.74 100 0
66 383.449 4.276 -6.196 -0.84 537.619 100 0
67 399.448 4.056 -5.746 -0.867 559.555 100 0
68 399.448 4.045 -5.785 -0.891 537.422 100 0
69 397.476 4.431 -6.226 -0.796 554.651 100 0
70 397.476 4.432 -6.227 -0.795 555.302 100 0
71 397.476 4.546 -6.414 -0.855 535.698 100 0
72 414.42 3.395 -5.122 -1.37 152.419 92.053 0
73 385.421 3.744 -5.232 -0.863 537.865 100 0
74 419.866 3.964 -5.355 -0.753 841.508 100 0
75 419.866 4.234 -5.967 -0.711 1323.7 100 0
76 419.866 4.234 -5.965 -0.709 1327.5 100 0
77 399.448 3.899 -5.261 -0.819 554.993 100 0
78 399.488 4.049 -5.795 -0.892 537.842 100 0
79 430.419 3.835 -5.386 -0.925 559.748 100 0
80 430.419 3.817 -5.384 -0.943 537.664 100 0
81 413.475 4.373 -6.187 -0.82 629.597 100 0
82 413.475 4.373 -6.189 -0.827 628.756 100 0
83 413.475 4.317 -6.811 -0.831 627.953 100 0
84 430.419 3.169 -4.724 -1.419 152.493 90.733 0
85 385.421 3.747 -5.248 -0.865 537.6 100 0
86 419.866 3.967 -5.371 -0.756 841.247 100 0
87 419.866 4.238 -5.985 -0.713 1325.4 100 0
88 419.866 4.237 -5.981 -0.712 1327 100 0
89 399.488 4.071 -5.639 -0.801 629.366 100 0
90 399.488 4.052 -5.811 -0.894 537.621 100 0
91 415.488 3.825 -5.413 -0.947 537.631 100 0
92 415.488 3.82 -5.4 -0.946 537.329 100 0
93 413.475 4.206 -5.84 -0.851 554.67 100 0
94 413.475 4.27 -5.841 -0.85 555.348 100 0
95 413.475 4.319 -6.224 -0.909 535.773 100 0
96 430.419 3.105 -5.215 -1.819 76.464 100 0
97 383.449 4.265 -6.004 -0.761 610.735 100 0
98 417.849 4.492 -6.138 -0.653 960.259 100 0
99 417.849 4.757 -6.745 -0.608 1503.2 100 0
100 417.849 4.757 -6.742 -0.607 1057.7 100 0
101 397.476 4.419 -6.013 -0.714 634.239 100 0
102 397.476 4.573 -6.574 -0.788 610.752 100 0
103 413.475 4.35 -6.125 -0.817 635.625 100 0
104 413.475 4.348 -6.174 -0.84 613.603 100 0
105 411.502 4.733 -6.608 -0.744 633.935 100 0
106 411.502 4.727 -6.583 -0.741 635.046 100 0
107 411.502 4.846 -6.983 -0.797 613.802 100 0
108 428.446 3.689 -5.493 -1.33 173.048 94.684 0
109 383.449 4.26 -6.003 -0.766 604.261 100 0
110 417.849 4.743 6.723 -0.531 1621 100 0
111 417.849 4.753 -6.745 -0.612 1491.4 100 0
112 417.849 4.752 -6.741 -0.612 1491.4 100 0
113 397.476 4.591 -6.337 -0.69 719.916 100 0
114 397.476 4.568 -6.572 -0.794 604.238 100 0
115 413.475 4.338 -6.14 -0.816 639.997 100 0
116 413.475 4.335 -6.159 -0.846 604.007 100 0
117 411.502 4.727 -6.576 -0.74 635.166 100 0
118 411.502 4.728 -6.577 -0.739 635.976 100 0
119 411.502 4.847 -6.978 -0.796 614.74 100 0
120 428.446 3.683 -5.491 1.334 171.268 94.578 0
121 383.449 4.24 -6.041 -0.824 537.518 100 0
122 417.849 4.459 -6.163 -0.715 841.028 100 0
123 417.849 4.732 -6.782 -0.672 1323 100 0
124 417.849 4.732 -6.779 -0.67 1326.8 100 0
125 397.476 4.566 -6.436 -0.759 629.303 100 0
126 397.476 4.547 -6.611 -0.852 537.621 100 0
127 413.475 4.332 -6.2 -0.886 559.473 100 0
128 413.475 4.314 -6.196 -0.904 537.353 100 0
129 411.502 4.874 -7.006 -0.786 628.359 100 0
130 411.502 4.874 -7.008 -0.868 535.69 100 0
131 411.502 4.817 -7.03 -0.785 629.302 100 0
132 428.446 3.663 -5.529 -1.392 152.406 100 0
133 400.393 3.084 -4.955 -1.583 99.2 87.144 0
134 434.838 3.32 -5.161 -1.481 151.165 88.074 0
135 434.838 3.589 -5.771 -1.476 238.332 89.909 0
136 434.838 3.588 -5.766 -1.475 238.614 89.904 0
137 414.42 3.238 -4.98 -1.517 102.649 88.292 0
138 414.42 3.402 -5.596 -1.662 96.633 96.633 0
139 430.419 3.187 -5.171 -1.682 102.649 88.907 0
140 430.419 3.156 -5.105 -1.678 99.192 87.566 0
141 469.283 3.792 -5.807 -1.316 382.654 91.037 0
142 469.283 3.792 -5.806 1.316 382.464 91.033 0
143 469.283 4.001 -6.298 -1.331 508.963 92.513 0
144 445.39 2.511 -4.45 -2.103 28.011 61.734 1
AQ4 393.441 4.236 -4.876 -0.477 2588.9 100 0
DJK 371.236 3.585 -5.168 -0.331 2157.2 100 0
Irressa 446.908 4.293 -4.967 -0.388 2646 100 0
AFN941 470.57 4.378 -6.791 -0.329 78.881 92.341 1
AMP-PNP 506.20 5.771 -6.753 -0.386 784.228 100 0

Table 3: Prediction of ADME properties of newly Designed isatin analogs using Qikprop.

All designed compounds showed ADME properties in acceptable range.

Conclusion

A number of newly designed isatin analogs 1-144 were docked into the active sites of five crystal structures of EGFR enzyme (PDB ID 2J5F, 2ITW, 2ITY , 2ITX and1M17) in order to investigate the possible interactions between the designed isatin analogs and the active site of the epidermal growth factor receptor (EGFR) kinase. The binding mode analysis of the compounds with the highest docking scores was carried out and were compared with that of the cocrystallized ligands DJK_3021_A, AFN941, irressa, AMP-PNP and AQ4 in the active sites of 2J5F, 2ITW, 2ITY, 2ITX and 1M17 respectively. It was found that compound 12 showed the highest docking score 8.31 in the active site of of the EGFR protein 2J5F. Compound 12 exhibited one hydrogen bond interaction and the dock score (-8.31) was also higher than that of the reference standard 2J5F (-7.665) while compound 68, compound 79, compound 80 and compound 108 showed highest docking score of -5.90, -7. 16, -6. 395 and -8. 14 respectively in the active sites of EGFR proteins 2ITW, 2ITY, 2ITX and 1M17. Compound 68 exhibited three hydrogen bond interactions and the dock score(-5. 90) was also higher than that of the reference standard AFN941 (-5.735). However, compound 79 showed two hydrogen bond interactions with a dock score (-7.16) which was quite higher than that of the reference standard Irressa (-4.65). Compound 80 showed two hydrogen bond interactions, however the dock score (-6.395) was much lower than that of the reference standard AMP-PNP (-9.101). Compound 108 showed two hydrogen bond interactions and the dock score (-8.14) was comparable to that of the reference standard AQ4 (-8.745). In all cases, the isatin moiety was oriented in a similar way as the reference ligand in the active sites of EGFR proteins 2J5F, 2ITW, 2ITY, 2ITX and 1M17 respectively. It was observed from the docking results that all isatin analogs have a common binding mode in the binding pockets of all the EGFR proteins. In all cases, hydrogen bonding interactions with the key residues were evident. ADME properties of all the newly designed compounds was studied by Qik Prop v3.0. All the designed compounds were found to exhibit lead like properties from the calculated ADME properties. These studies indicate that the newly designed isatin analogs may have a good binding affinity for EGFR enzyme. It can be concluded that the isatin moiety flanked by aryl rings substituted particularly with methyl, methoxy and nitro groups with a CH2CONH linker at the first position of the isatin ring structure may serve as a prominent scaffold for further synthesis of novel isatin analogs which could act as EGFR kinase inhibitors with promising anticancer activity.

Acknowledgements

The authors BD gratefully acknowledges the University Grants Commission- Basic Science Research (UGC-BSR) for the award of fellowship during the work.

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