Fig 1.
Workflow of this study.
Table 1.
Libdock and Autodock vina、pka scores of 20 selected molecules and positive control AG-636 with DHODH. In addition, the DUH (crystal inhibitor) also performed docking and was shown in S3 Fig. It can be seen that two hydrogen bond interactions were formed, and the final docking score was −15.6344.
Table 2.
The number of features, feature set, sensitivity, specificity, and ROC curve of 10 pharmacophore models based on the common characteristics of molecules.
Fig 2.
The pharmacophore model and Receiver operating characteristic (ROC) curve validation.
(A) Pharmacophore model CF_8. Hydrophobic group features are represented by blue spheres, hydrogen bond donor features are represented by green spheres, and aromatic ring features are represented by orange spheres (B) ROC curve.
Table 3.
Structure, Libdock of the positive control AG636 and six lead molecules.
Table 4.
ADME prediction results of 7 lead compounds.
Table 5.
Structure, Libdock, and CDOCKER energy scores of original compound 1281 and its derivatives 1281_65 and 1281_66.
Fig 3.
2D interaction diagram and 3D interaction diagram of the original compound 1281 and the positive control AG636.
(A) 2D interaction plot of the original compound 1281. Hydrogen bonds are shown as green dashed lines, Hydrophobicity is in red lines. (B) 3D interaction plot of the original compound 1281. Hydrogen bonds are shown as purple dashed lines. (C) 2D interaction plot of the positive control AG636. Hydrogen bonds are shown as green dashed lines, and Hydrophobicity is in red lines. (D) 3D interaction plot of the positive control AG636. Hydrogen bonds are shown as purple dashed lines.
Fig 4.
2D interaction diagram and 3D interaction diagram of compound 1281_65 and compound 1281_66.
(A) 2D interaction diagram of compound 1281_65. Hydrogen bonds are shown as green dashed lines, Hydrophobicity is in red lines. (B) 3D interaction diagram of compound 1281_65. Hydrogen bonds are shown as purple dashed lines. (C) 2D interaction diagram of compound 1281_66. Hydrogen bonds are shown as green dashed lines, Hydrophobicity is in red lines. (D) 3D interaction diagram of compound 1281_66. Hydrogen bonds are shown as purple dashed lines.
Fig 5.
Molecular dynamics analysis of compounds 65(blue) and 66(black) and DUH(red) with DHODH.
(A) The RMSD of compounds 65 and 66、DUH with DHODH. Compound 65 is shown as blue lines, compound 66 is in the black line. DUH is in the red line. (B) The RMSF of compounds 65 and 66 and DUH with DHODH. Compound 65 is shown as blue lines, compound 66 is in the black line. DUH is in the red line. (C) The Rg of compounds 65 and 66 and DUH with DHODH. Compound 65 is shown as blue lines, compound 66 is in the black line. DUH is in the red line. (D) The Area of compounds 65 and 66 and DUH with DHODH. Compound 65 is shown as blue lines, compound 66 is in the black line. DUH is in the red line. (E) The Hydrogen bond number of compound 65 with DHODH. (F) The Hydrogen bond number of compound 66 with DHODH. (G) The Hydrogen bond number of compound DUH with DHODH. (H) The total energy of compounds 65 and 66 and DUH with DHODH. Compound 65 is shown as blue lines, compound 66 is in the black line. DUH is in the red line.
Table 6.
The binding energy of binding for compounds 65 and 66、DUH with DHODH.
Fig 6.
Residue decomposition diagram of binding energy.
(A) Compound 65 with DHODH (black). (B) Compound 66 with DHODH (red). (C) Compound DUH with DHODH (blue).
Fig 7.
Principal component analysis plot for the complex 65 and 66 and DUH.
(A-L) The Fig shows the scatter plot among the first three principal components (PC1, PC2, and PC3) of the 65 system, with the blue region exhibiting the most pronounced motion, the white region exhibiting intermediate motion, and the red region exhibiting lesser motion. (E-H) The Fig shows the scatter plot among the first three principal components (PC1, PC2, and PC3) of the 66 system, with the blue region exhibiting the most pronounced motion, the white region exhibiting intermediate motion, and the red region exhibiting lesser motion. (I-L)The Fig shows the scatter plot among the first three principal components (PC1, PC2, and PC3) of the DUH system, with the blue region exhibiting the most pronounced motion, the white region exhibiting intermediate motion, and the red region exhibiting lesser motion.
Fig 8.
Dynamic interrelationship diagram of the complex.
(A) Compound 65 with DHODH (B) Compound 66 with DHODH. (C) DUH with DHODH. Positive correlations between residues are shown in cyan and negative correlations are shown in light green.
Fig 9.
PCA-based Free-energy topography and variation of the lowest energy conformation of the protein-ligand.
(A) Compound 65 with DHODH (B) Compound 66 with DHODH. (C) DUH with DHODH.