SUPPORTING INFORMATION

Molecular docking, MM/GBSA and 3D-QSAR studies on EGFR inhibitors

RAJU BATHINI, SREE KANTH SIVAN, SABIHA FATIMA and VIJJULATHA MANGA*

Molecular Modeling and Medicinal Chemistry Group, Department of Chemistry,

University College of Science, Osmania University, Hyderabad 500 007, India

Email:

*For correspondence

Table of Contents:

S.No. / Material / Descriptions
1 / Supplementary Figure S1 / Superimposition of structure pose and docked pose of co-crystalized ligand with RMS deviation of 1.92 Å.
2 / Supplementary Table S1 / ADME properties of Molecules
3 / Supplementary Table S2 / Toxicity profile of molecules obtained from pKCSM online server

Figure S1: Superimposition of structure pose and docked pose of co-crystalized ligand with RMS deviation of 1.92 Å.

Table S1: ADME properties of Molecules

Moleculea / QPlogPo/wb / QPlogSc / QPlogBBd / QPPCacoe / QPPMDCKf / % Human oral absorptiong
Designed Molecules
N1 / 7.986 / -9.342 / -0.002 / 828.497 / 1761.994 / 100.000
N2 / 8.506 / -9.708 / -0.045 / 889.366 / 1879.354 / 100.000
N3 / 8.916 / -9.528 / -0.017 / 889.370 / 1868.771 / 100.000
N4 / 7.592 / -9.76 / -1.090 / 209.935 / 400.956 / 89.689
N5 / 7.215 / -9.288 / -1.220 / 135.592 / 251.439 / 80.633
Dataset molecules
1 / 7.395 / -8.459 / -0.231 / 2771.73 / 5427.231 / 100
2 / 5.588 / -5.756 / -1.129 / 83.807 / 112.9 / 68.17
3 / 6.513 / -5.914 / -0.073 / 564.828 / 888.224 / 88.42
4 / 7.919 / -9.316 / 0.225 / 1112.919 / 2413.169 / 100
5 / 8.071 / -9.518 / 0.297 / 1108.354 / 3526.745 / 100
6 / 7.285 / -8.843 / 0.194 / 1067.196 / 2306.215 / 100
7 / 7.864 / -9.529 / 0.3 / 1087.15 / 3920.574 / 100
8 / 5.789 / -4.722 / 0.127 / 687.905 / 1124.403 / 85.708
9 / 5.626 / -4.534 / -0.374 / 404.31 / 637.221 / 80.627
10 / 4.486 / -5.494 / -0.148 / 2269.648 / 4702.033 / 100
11 / 5.074 / -6.282 / -0.095 / 2656.372 / 5563.135 / 100
12 / 5.454 / -6.838 / -0.407 / 1693.932 / 3250.333 / 100
13 / 6.326 / -7.631 / 0.088 / 3077.936 / 10000 / 100
14 / 6.512 / -7.722 / -0.121 / 3534.494 / 7585.288 / 100
15 / 4.629 / -5.747 / -0.051 / 822.019 / 1739.782 / 100
16 / 5.004 / -6.169 / -0.127 / 819.207 / 1733.243 / 82.47
17 / 6.475 / -7.273 / 0.399 / 1278.162 / 2801.742 / 94.541
18 / 6.281 / -7.416 / 0.156 / 1070.032 / 2313.1 / 100
19 / 7.2 / -8.475 / 0.263 / 1173.15 / 2555.193 / 100
20 / 5.366 / -6.962 / -0.381 / 466.559 / 942.705 / 80.218
21 / 5.194 / -6.865 / -0.432 / 388.002 / 1036.536 / 77.775
22 / 5.025 / -6.702 / -0.534 / 359.342 / 710.927 / 76.189
23 / 6.045 / -8.463 / -0.848 / 225.935 / 578.704 / 78.553
24 / 4.285 / -4.656 / -1.057 / 563.405 / 954.359 / 88.313
25 / 5.741 / -7.262 / -0.143 / 504.788 / 1344.088 / 83.027
26 / 5.933 / -7.099 / 0.24 / 1104.009 / 2392.176 / 100
27 / 5.47 / -6.387 / 0.302 / 1062.99 / 2296.145 / 100
28 / 5.206 / -6.753 / -0.304 / 634.161 / 1314.248 / 81.664
29 / 7.046 / -8.358 / 0.149 / 1080.285 / 2336.753 / 100
30 / 6.529 / -7.496 / 0.417 / 248.176 / 527.048 / 82.12
31 / 3.656 / -5.366 / -0.832 / 733.486 / 960.448 / 100
32 / 4.797 / -6.916 / -0.769 / 887.86 / 1274.949 / 100
33 / 3.464 / -4.985 / -0.212 / 1984.424 / 2872.695 / 100
34 / 4.002 / -6.851 / -1.011 / 362.982 / 1208.981 / 96.194
35 / 4.941 / -5.818 / -0.625 / 1963.488 / 1025.838 / 100
36 / 5.11 / -7.443 / -0.856 / 890.333 / 941.369 / 96.701
37 / 6.223 / -8.565 / -1.168 / 126.091 / 231.611 / 75.064
38 / 4.321 / -5.31 / -0.793 / 105.921 / 182.666 / 75.531
39 / 3.01 / -2.638 / -0.423 / 28.833 / 17.184 / 57.741
40 / 6.037 / -8.267 / -0.72 / 1455.585 / 2915.349 / 100
41 / 6.528 / -9.593 / -1.847 / 422.637 / 765.649 / 86.251
42 / 5.392 / -9.047 / -1.656 / 369.274 / 661.798 / 78.55
43 / 8.522 / -10.981 / -0.343 / 2324.471 / 10000 / 100
44 / 8.326 / -10.759 / -0.804 / 1677.379 / 6147.888 / 100
45 / 8.359 / -11.1 / -0.644 / 1589.09 / 10000 / 100

a. Data set molecules and designed molecules.

b. Predicted octanol/water partition coefficient log P

c. Predicted aqueous solubility’s in mol/L

d. Predicted BBB permeability

e. Predicted Caco cell permeability in nm/s

f. Predicted apparent MDCK cell permeability in nm/s

g. Percentage of human oral absorption.

Table S2: Toxicity profile of molecules obtained from pKCSM online server

MOLECULE / CYP2D6
substrate / CYP3A4
substrate / CYP1A2
inhibitior / CYP2C19
inhibitior / CYP2C9
inhibitior / CYP2D6
inhibitior / CYP3A4
inhibitior / Total
Clearance / Renal
OCT2
substrate / AMES
toxicity / Max.
tolerated
dose
(human) / hERG I
nhibitor / hERG II
inhibitor / Oral
Rat
Acute
Toxicity
(LD50) / Oral
Rat
Chronic
Toxicity
(LOAEL) / Hepato
toxicity / T.
Pyriformis
toxicity / Minnow
toxicity
N2 / No / Yes / No / No / No / No / Yes / 0.633 / No / No / 0.698 / No / Yes / 2.699 / 2.681 / Yes / 0.295 / -2.383
N3 / No / Yes / No / No / No / No / Yes / 0.545 / No / No / -0.675 / No / Yes / 3.088 / 0.172 / No / 0.389 / -0.651
N4 / No / Yes / No / No / No / No / Yes / 0.534 / No / No / -0.701 / No / Yes / 2.98 / 0.49 / Yes / 0.354 / -0.177
N5 / No / Yes / No / No / No / No / Yes / 0.604 / No / No / -0.489 / No / Yes / 2.96 / 0.624 / Yes / 0.449 / -0.096
N1 / No / Yes / No / No / No / No / Yes / 0.658 / No / No / -0.418 / No / Yes / 3.115 / 0.47 / Yes / 0.671 / -0.269
1 / No / Yes / No / Yes / Yes / No / Yes / -0.18 / No / No / 1.047 / No / Yes / 2.663 / 2.241 / Yes / 0.453 / -1.096
2 / No / Yes / No / No / No / No / Yes / 0.782 / No / No / -0.408 / No / Yes / 2.842 / 0.997 / Yes / 0.489 / 0.354
3 / No / Yes / No / No / No / No / Yes / 0.915 / No / No / -0.392 / No / Yes / 2.986 / 0.785 / Yes / 0.723 / 0.085
4 / No / Yes / No / No / No / No / Yes / 0.978 / No / No / -0.578 / No / Yes / 3 / 0.874 / Yes / 0.512 / 0.213
5 / No / Yes / No / No / No / No / Yes / 0.896 / No / No / -0.601 / No / Yes / 3.079 / 0.82 / Yes / 0.478 / 0.232
6 / No / Yes / No / No / No / No / Yes / 1.004 / No / No / -0.553 / No / Yes / 3.063 / 0.9 / Yes / 0.516 / 0.363
7 / No / Yes / No / No / No / No / Yes / 1.092 / No / No / -0.538 / No / Yes / 3.116 / 0.801 / Yes / 0.516 / 0.084
8 / No / Yes / No / No / No / No / Yes / 0.741 / No / No / -0.356 / No / Yes / 2.943 / 1.008 / Yes / 0.804 / 0.352
9 / No / Yes / No / No / No / No / Yes / 0.928 / No / No / -0.338 / No / Yes / 2.897 / 0.776 / Yes / 0.468 / 0.054
10 / No / Yes / Yes / Yes / No / No / No / 0.673 / No / No / 0.494 / No / Yes / 3.105 / 0.951 / Yes / 2.092 / 0.632
11 / No / Yes / Yes / Yes / No / No / No / 0.659 / No / No / 0.431 / No / Yes / 3.124 / 0.892 / Yes / 2.075 / 0.535
12 / No / Yes / No / Yes / No / No / Yes / 0.642 / No / No / -0.049 / No / Yes / 3.282 / 0.689 / Yes / 1.17 / 0.331
13 / No / Yes / Yes / Yes / No / No / Yes / 0.802 / No / No / 0.018 / No / Yes / 3.418 / 0.52 / Yes / 1.232 / 0.024
14 / No / Yes / No / No / Yes / No / Yes / 0.557 / No / No / -0.07 / No / Yes / 3.365 / 0.516 / Yes / 1.1 / 0.096
15 / No / Yes / No / No / Yes / No / Yes / 0.692 / No / No / -0.215 / No / Yes / 3.119 / 0.882 / Yes / 0.65 / 0.348
16 / No / Yes / No / No / Yes / No / Yes / 0.753 / No / No / -0.223 / No / Yes / 3.114 / 0.789 / Yes / 0.602 / 0.183
17 / No / Yes / No / No / No / No / Yes / 0.731 / No / No / -0.518 / No / Yes / 3.227 / 0.556 / Yes / 0.507 / -0.038
18 / No / Yes / No / No / No / No / Yes / 0.768 / No / No / -0.29 / No / Yes / 3.118 / 0.818 / Yes / 0.791 / 0.189
19 / No / Yes / No / No / No / No / Yes / 0.715 / No / No / -0.619 / No / Yes / 3.116 / 0.676 / Yes / 0.472 / 0.072
20 / No / Yes / No / No / No / No / Yes / 0.927 / No / No / -0.3 / No / Yes / 2.977 / 0.873 / Yes / 0.537 / 0.23
21 / No / Yes / No / No / No / No / Yes / 0.83 / No / No / -0.271 / No / Yes / 3.038 / 0.858 / Yes / 0.514 / 0.327
22 / No / Yes / No / No / No / No / Yes / 0.939 / No / No / -0.258 / No / Yes / 2.969 / 0.953 / Yes / 0.563 / 0.348
23 / No / Yes / No / No / No / No / Yes / 1.181 / No / No / -0.243 / No / Yes / 2.953 / 1.057 / Yes / 0.573 / 0.469
24 / No / Yes / No / No / No / No / Yes / 0.552 / No / No / 0.025 / No / Yes / 3.01 / 0.856 / Yes / 0.624 / 0.425
25 / No / Yes / No / No / No / No / Yes / 0.973 / No / No / -0.307 / No / Yes / 2.999 / 1.108 / Yes / 0.613 / 0.57
26 / No / Yes / No / No / Yes / No / Yes / 0.715 / No / No / -0.272 / No / Yes / 3.107 / 0.911 / Yes / 0.857 / 0.355
27 / No / Yes / No / No / No / No / Yes / 0.679 / No / No / -0.249 / No / Yes / 3.089 / 1.003 / Yes / 0.921 / 0.52
28 / No / Yes / No / No / No / No / Yes / 0.451 / No / No / -0.328 / No / Yes / 3.05 / 0.933 / Yes / 0.603 / 0.39
29 / No / Yes / No / No / No / No / Yes / 1.097 / No / No / -0.243 / No / Yes / 2.971 / 1.017 / Yes / 0.884 / 0.331
30 / No / Yes / No / No / No / No / Yes / 0.647 / No / No / -0.335 / No / Yes / 3.077 / 0.776 / Yes / 0.689 / 0.004
31 / No / Yes / Yes / Yes / No / No / No / 0.332 / No / No / 0.295 / No / Yes / 3.002 / 1.059 / Yes / 1.798 / 0.585
32 / No / Yes / No / No / No / No / No / 0.726 / No / No / -0.094 / No / Yes / 3.032 / 1.144 / Yes / 1.154 / 1.02
33 / No / Yes / Yes / No / No / No / No / 0.704 / No / No / 0.419 / No / Yes / 3.048 / 1.393 / Yes / 1.745 / 1.055
34 / No / Yes / No / No / No / No / Yes / 0.792 / No / No / -0.138 / No / Yes / 3.198 / 0.986 / Yes / 0.978 / 0.701
35 / No / Yes / Yes / Yes / No / No / No / 0.749 / No / No / 0.407 / No / Yes / 2.667 / 1.7 / Yes / 1.905 / 0.625
36 / No / Yes / No / No / No / No / No / 0.833 / No / No / -0.126 / No / Yes / 2.96 / 1.008 / Yes / 1.174 / 0.571
37 / No / Yes / No / No / No / No / Yes / 0.937 / No / No / -0.531 / No / Yes / 2.977 / 0.709 / Yes / 0.374 / 0.217
38 / No / Yes / No / No / No / No / Yes / 1.117 / No / No / -0.735 / No / Yes / 2.82 / 0.952 / Yes / 0.308 / 0.484
39 / No / Yes / No / No / No / No / Yes / 1.172 / No / No / -0.713 / No / Yes / 2.772 / 1.335 / Yes / 0.322 / 0.807
40 / No / Yes / No / No / Yes / No / Yes / 0.644 / No / No / -0.238 / No / Yes / 3.333 / 0.456 / Yes / 0.732 / 0.033
41 / No / Yes / No / No / No / No / Yes / 0.772 / No / No / -0.29 / No / Yes / 3.056 / 0.38 / Yes / 0.431 / -0.162
42 / No / Yes / No / No / Yes / No / Yes / 0.594 / No / No / -0.295 / No / Yes / 3.225 / 0.434 / Yes / 0.576 / 0.039
43 / No / Yes / No / No / No / No / Yes / 0.619 / No / No / -0.576 / No / Yes / 3.274 / 0.037 / Yes / 0.347 / -0.325
44 / No / Yes / No / No / No / No / Yes / 0.576 / No / No / -0.591 / No / Yes / 3.26 / 0.045 / Yes / 0.37 / -0.477
45 / No / Yes / No / No / No / No / Yes / 0.491 / No / No / -0.547 / No / Yes / 3.18 / 0.033 / No / 0.33 / -0.309