Author Contributions
Conceptualization, J.L., Q.Y. and C.F.; methodology, J.L., Q.Y. and C.F.; software, Q.Y. and C.F.; validation, J.L., Q.Y. and C.F.; formal analysis, J.L., Q.Y. and C.F.; investigation, J.L. and Q.Y.; resources, J.L.; data curation, J.L., Q.Y. and C.F.; writing—original draft preparation, Q.Y. and C.F.; writing—review and editing, J.L., Q.Y. and C.F.; visualization, Q.Y. and C.F.; supervision, J.L.; project administration, J.L. All authors have read and agreed to the published version of the manuscript.
Figure 1.
The studied c-Met inhibitors. (A) is the common atoms (represented as balls) used for molecular alignment in compound 4. (B) is the atom-based alignment figure (Alignment A). (C) is the docking-based alignment figure (Alignment B).
Figure 1.
The studied c-Met inhibitors. (A) is the common atoms (represented as balls) used for molecular alignment in compound 4. (B) is the atom-based alignment figure (Alignment A). (C) is the docking-based alignment figure (Alignment B).
Figure 2.
The scatter plots of experimental values vs. predicted values using CoMFA and CoMSIA based on atom-based approach (Alignment A) and docking-based approach (Alignment B). (A) is the CoMFA model of Alignment A, (B) is the CoMSIA model of Alignment A, (C) is the CoMFA model of Alignment B, (D) is the CoMSIA model of Alignment B.
Figure 2.
The scatter plots of experimental values vs. predicted values using CoMFA and CoMSIA based on atom-based approach (Alignment A) and docking-based approach (Alignment B). (A) is the CoMFA model of Alignment A, (B) is the CoMSIA model of Alignment A, (C) is the CoMFA model of Alignment B, (D) is the CoMSIA model of Alignment B.
Figure 3.
The errors between the experimental values and the predicted values for CoMFA and CoMSIA based on ligand-based approach and receptor-based approach were shown in panels (A–D), respectively. The shorter the bar is, the better the model prediction is.
Figure 3.
The errors between the experimental values and the predicted values for CoMFA and CoMSIA based on ligand-based approach and receptor-based approach were shown in panels (A–D), respectively. The shorter the bar is, the better the model prediction is.
Figure 4.
The CoMFA STDEV × COEFF contour maps based on template compound 4. (A) The steric field. (B) The electrostatic field.
Figure 4.
The CoMFA STDEV × COEFF contour maps based on template compound 4. (A) The steric field. (B) The electrostatic field.
Figure 5.
The CoMSIA STDEV × COEFF contour maps matched with template compound 4 based on Alignment A. (A) The steric field. (B) The electrostatic field. (C) The hydrogen bond donor field. (D) The hydrogen bond acceptor field.
Figure 5.
The CoMSIA STDEV × COEFF contour maps matched with template compound 4 based on Alignment A. (A) The steric field. (B) The electrostatic field. (C) The hydrogen bond donor field. (D) The hydrogen bond acceptor field.
Figure 6.
2D diagram of docking interaction of compound 4 with c-Met Kinase 3CCN.
Figure 6.
2D diagram of docking interaction of compound 4 with c-Met Kinase 3CCN.
Figure 7.
The docking-based CoMFA STDEVCOEFF contour maps (A) The steric field. (B) The electrostatic field.
Figure 7.
The docking-based CoMFA STDEVCOEFF contour maps (A) The steric field. (B) The electrostatic field.
Figure 8.
The docking-based CoMSIA STDEV × COEFF contour maps (A) The steric field. (B) The electrostatic field. (C) The hydrogen bond donor field. (D) The hydrogen bond acceptor field.
Figure 8.
The docking-based CoMSIA STDEV × COEFF contour maps (A) The steric field. (B) The electrostatic field. (C) The hydrogen bond donor field. (D) The hydrogen bond acceptor field.
Figure 9.
Root mean square deviation (RMSD) of the system. (A) the RMSD of the protein backbone atoms of the complex; (B) the RMSD of the heavy atoms (all non-hydrogen atoms) of the ligand; (C) the RMSD of the Cα atoms the binding site that the residues within 5 Å around the ligand.
Figure 9.
Root mean square deviation (RMSD) of the system. (A) the RMSD of the protein backbone atoms of the complex; (B) the RMSD of the heavy atoms (all non-hydrogen atoms) of the ligand; (C) the RMSD of the Cα atoms the binding site that the residues within 5 Å around the ligand.
Figure 10.
The ligand location comparison of the initial structure and after MD stabilized conformation. (A) Overlay of the first frame structure and the last frame structure of the trajectory, this green is the protein structure of the first frame and this red is the small molecule structure of the first frame, this blue is the protein structure of the last frame and this yellow is the small molecule structure of the last frame; (B) the amino acid residues around the binding site.
Figure 10.
The ligand location comparison of the initial structure and after MD stabilized conformation. (A) Overlay of the first frame structure and the last frame structure of the trajectory, this green is the protein structure of the first frame and this red is the small molecule structure of the first frame, this blue is the protein structure of the last frame and this yellow is the small molecule structure of the last frame; (B) the amino acid residues around the binding site.
Figure 11.
Root mean square fluctuation (RMSF) of the system.
Figure 11.
Root mean square fluctuation (RMSF) of the system.
Figure 12.
Contribution of partial residues calculated by decomposing the binding energy.
Figure 12.
Contribution of partial residues calculated by decomposing the binding energy.
Figure 13.
Graphical representation of SARs derived from CoMFA and CoMSIA analysis. All the groups mentioned above are beneficial to the inhibition activity.
Figure 13.
Graphical representation of SARs derived from CoMFA and CoMSIA analysis. All the groups mentioned above are beneficial to the inhibition activity.
Table 1.
The studied chemical IDs (the detailed molecular structures were listed in the
Supplementary Materials) and corresponding experimental/predicted inhibition activities.
Table 1.
The studied chemical IDs (the detailed molecular structures were listed in the
Supplementary Materials) and corresponding experimental/predicted inhibition activities.
No. | Activity (pIC50) |
---|
Exp. | Alignment A | Alignment B |
---|
CoMFA | CoMSIA | CoMFA | CoMSIA |
---|
1 | 6.494 | 6.684 | 6.634 | 6.447 | 6.437 |
2 | 7.004 | 6.848 | 6.958 | 6.966 | 6.97 |
3 | 6.553 | 6.338 | 6.464 | 6.669 | 6.587 |
4 | 7.785 | 7.567 | 7.687 | 7.789 | 7.775 |
5 | 7.670 | 7.766 | 7.584 | 7.615 | 7.764 |
6 | 6.993 | 6.988 | 7.108 | 6.914 | 6.987 |
7 | 7.210 | 7.267 | 7.155 | 7.218 | 7.248 |
8 | 6.640 | 6.597 | 6.632 | 6.726 | 6.687 |
9 | 7.347 | 7.440 | 7.474 | 7.367 | 7.349 |
10 * | 7.231 | 7.332 | 7.333 | 7.248 | 7.416 |
11 * | 6.641 | 6.459 | 6.636 | 6.791 | 6.918 |
12 * | 7.419 | 7.457 | 7.310 | 7.223 | 6.934 |
13 | 6.819 | 6.718 | 6.790 | 6.663 | 6.718 |
14 | 7.577 | 7.541 | 7.547 | 7.569 | 7.579 |
15 | 7.179 | 7.432 | 7.372 | 7.116 | 7.11 |
16* | 6.885 | 6.841 | 6.917 | 6.884 | 6.909 |
17 | 7.297 | 7.284 | 7.288 | 7.333 | 7.223 |
18 | 7.588 | 7.324 | 7.259 | 7.553 | 7.6 |
19 | 7.343 | 7.426 | 7.301 | 7.425 | 7.373 |
20 | 7.348 | 7.358 | 7.332 | 7.365 | 7.362 |
21 | 6.619 | 6.745 | 7.018 | 6.64 | 6.577 |
22 | 7.115 | 7.019 | 7.084 | 7.096 | 7.031 |
23 * | 7.088 | 7.021 | 7.145 | 6.87 | 7.024 |
24 | 7.656 | 7.647 | 7.685 | 7.789 | 7.67 |
25 | 6.996 | 6.892 | 6.786 | 6.97 | 7.026 |
26 | 7.188 | 7.193 | 7.239 | 7.158 | 7.283 |
27 | 7.009 | 7.070 | 7.000 | 6.965 | 6.968 |
28 | 6.707 | 6.791 | 6.750 | 6.707 | 6.655 |
29 | 6.761 | 6.771 | 6.784 | 6.747 | 6.755 |
30 | 5.920 | 5.766 | 5.797 | 5.833 | 5.736 |
31 | 5.155 | 5.450 | 5.600 | 5.354 | 5.46 |
32 * | 6.222 | 6.237 | 6.356 | 6.369 | 6.263 |
33 * | 5.386 | 6.036 | 6.075 | 5.984 | 5.505 |
34 | 6.319 | 6.040 | 5.980 | 6.366 | 6.347 |
35 | 5.886 | 5.821 | 5.833 | 5.75 | 5.762 |
36 | 5.943 | 6.084 | 6.026 | 6.063 | 6.009 |
37 | 6.387 | 6.375 | 6.269 | 6.435 | 6.491 |
38 | 6.251 | 6.223 | 6.193 | 6.171 | 6.13 |
39 | 6.292 | 6.356 | 6.178 | 6.304 | 6.357 |
40 | 6.678 | 6.843 | 6.892 | 6.683 | 6.681 |
41 | 5.943 | 6.006 | 5.969 | 5.9 | 5.963 |
42 * | 6.468 | 6.887 | 6.863 | 6.102 | 6.202 |
Table 2.
Summary of the CoMFA and CoMSIA models for alignment-A and alignment-B.
Table 2.
Summary of the CoMFA and CoMSIA models for alignment-A and alignment-B.
PLS Statistic | Alignment-A | Alignment-B |
---|
CoMFA | CoMSIA | CoMFA | CoMSIA |
---|
Q2 | 0.596 | 0.646 | 0.563 | 0.568 |
ONC | 2 | 2 | 6 | 2 |
R2 | 0.950 | 0.931 | 0.985 | 0.983 |
SEE | 0.150 | 0.175 | 0.085 | 0.089 |
R2pred | 0.839 | 0.840 | 0.821 | 0.854 |
F | 160.303 | 76.047 | 286.459 | 260.420 |
Field distribution | - | - | - | - |
S (Field distribution) | 47.2% | 19.7% | 54.00% | 14.30% |
E (Field distribution) | 52.8% | 33.2% | 46.00% | 33.20% |
A (Field distribution) | - | 19.3% | - | 30.00% |
D (Field distribution) | - | 27.8% | - | 22.5% |
Table 3.
Different field combinations in CoMSIA analysis keeping S and E fields in all cases for alignment-A.
Table 3.
Different field combinations in CoMSIA analysis keeping S and E fields in all cases for alignment-A.
Field | ONC | Q2 | R2 | SEE | F | Rate of Contribution |
---|
SED | 2 | 0.628 | 0.934 | 0.172 | 79.479 | 0.268:0.525:0.207 |
SEA | 2 | 0.643 | 0.943 | 0.160 | 92.376 | 0.277:0.392:0.331 |
SEH | 2 | 0.603 | 0.923 | 0.185 | 67.394 | 0.235:0.440:0.325 |
SEHA | 2 | 0.620 | 0.929 | 0.179 | 73.004 | 0.191:0.292:0.255:0.262 |
SEHD | 2 | 0.602 | 0.922 | 0.186 | 66.626 | 0.184:0.375:0.273:0.168 |
SEAD | 2 | 0.646 | 0.931 | 0.175 | 76.047 | 0.197:0.332:0.193:0.278 |
SEHAD | 2 | 0.622 | 0.922 | 0.187 | 66.342 | 0.148:0.253:0.160:0.227:0.212 |
Table 4.
Different field combinations in CoMSIA analysis for alignment-B.
Table 4.
Different field combinations in CoMSIA analysis for alignment-B.
Field | ONC | Q2 | R2 | SEE | F | Rate of Contribution |
---|
SED | 3 | 0.556 | 0.981 | 0.094 | 229.485 | 0.255:0.515:0.230 |
SEA | 3 | 0.55 | 0.976 | 0.105 | 184.036 | 0.219:0.477:0.304 |
SEH | 2 | 0.52 | 0.984 | 0.087 | 272.649 | 0.182:0.446:0.372 |
SEHA | 2 | 0.53 | 0.985 | 0.082 | 303.786 | 0.136:0.339:0.306:0.219 |
SEHD | 2 | 0.526 | 0.991 | 0.065 | 491.572 | 0.154:0.358:0.163:0.325 |
SEAD | 3 | 0.561 | 0.981 | 0.095 | 228.254 | 0.178:0.378:0.264:0.180 |
SEHDA | 2 | 0.536 | 0.988 | 0.073 | 385.686 | 0.117:0.286:0.197:0.138:0.262 |
Table 5.
Binding free energy of the system and energy contribution of each component.
Table 5.
Binding free energy of the system and energy contribution of each component.
Interaction | Contribution (kcal/mol) | Standard Deviation |
---|
∆EvdW | −32.99 | 3.62 |
∆Eele | 36.18 | 24.78 |
∆GGB | −25.82 | 23.74 |
∆GSA | −4.45 | 0.38 |
∆Egas | 3.19 | 24.72 |
∆Esolv | −30.27 | 23.64 |
∆Gbind | −27.08 | 3.80 |
Table 6.
Hydrogen bond distribution for the system.
Table 6.
Hydrogen bond distribution for the system.
Acceptor | DonorH | Donor | Frac |
---|
ASP_1222@OD2 | MOL@H22 | MOL@N4 | 0.6651 |
ASP_1222@OD2 | MOL@H20 | MOL@N3 | 0.6569 |
ASP_1222@OD1 | MOL@H20 | MOL@N3 | 0.6431 |
ASP_1222@OD1 | MOL@H22 | MOL@N4 | 0.6178 |