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. 2023 May 15;13(22):14808-14824.
doi: 10.1039/d3ra01316b.

In silico studies of a novel scaffold of benzoxazole derivatives as anticancer agents by 3D-QSAR, molecular docking and molecular dynamics simulations

Yuhan Jiang  1 , Wei Yang  2 , Fangfang Wang  1 , Bo Zhou  3
Affiliations

In silico studies of a novel scaffold of benzoxazole derivatives as anticancer agents by 3D-QSAR, molecular docking and molecular dynamics simulations

Yuhan Jiang et al. RSC Adv. .

Abstract

The vascular endothelial growth factor receptor-2 kinases (VEGFR-2) expressed on tumor cells and vessels are attractive targets for cancer treatment. Potent inhibitors for the VEGFR-2 receptor are novel strategies to develop anti-cancer drugs. In this work, template ligand-based 3D-QSAR studies were performed on a series of benzoxazole derivatives toward different cell lines (HepG2, HCT-116 and MCF-7). Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques were used to generate 3D-QSAR models. Good predictability was derived for the optimal CoMFA models (HepG2: Rcv2 = 0.509, Rpred2 = 0.5128; HCT-116: Rcv2 = 0.574, Rpred2 = 0.5597; MCF-7: Rcv2 = 0.568, Rpred2 = 0.5057) and CoMSIA models (HepG2: Rcv2 = 0.711, Rpred2 = 0.6198; HCT-116: Rcv2 = 0.531, Rpred2 = 0.5804; MCF-7: Rcv2 = 0.669, Rpred2 = 0.6577). In addition, the contour maps derived from CoMFA and CoMSIA models were also generated to illustrate the relationship between different fields and the inhibitory activities. Moreover, molecular docking and molecular dynamics (MD) simulations were also conducted to understand the binding modes and the potential interactions between the receptor and the inhibitors. Some key residues (Leu35, Val43, Lys63, Leu84, Gly117, Leu180 and Asp191) were pointed out for stabilizing the inhibitors in the binding pocket. The binding free energies for the inhibitors agreed well with the experimental inhibitory activity and indicated that steric, electrostatic and hydrogen bond interactions are the main driving force for inhibitor-receptor binding. Overall, a good consistency between theoretical 3D-SQAR and molecular docking and MD simulation studies would provide directions for the design of new candidates, avoiding time-consuming and costly synthesis and biological evaluations. On the whole, the results derived from this study could expand the understanding of benzoxazole derivatives as anticancer agents and would be of great help in lead optimization for early drug discovery of highly potent anticancer activity targeting VEGFR-2.

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Conflict of interest statement

The authors declare that there are no conflicts of interest.

Figures

Fig. 1
Fig. 1. (A) Cpd11 is used as a template for alignment. The common substructure is shown in blue. (B) Present the alignment for HepG2 compounds. (C) Present the alignment for HCT-116 compounds. (D) Present the alignment for MCF-7 compounds.
Fig. 2
Fig. 2. Graphs of the predicted versus the experimental pIC50 values of the optimal models for (A) CoMFA model for HepG2. (B) CoMSIA model for HepG2. (C) CoMFA model for HCT-116. (D) CoMSIA model for HCT-116. (E) CoMFA model for MCF-7. (F) CoMSIA model for MCF-7.
Fig. 3
Fig. 3. CoMFA StDev*Coeff contour plots for HepG2 compounds in combination of Cpd11. (A) The steric contour map, where the green and yellow contours represent 80% and 20% level contributions, respectively. (B) The electrostatic contour map, where the blue and red contours represent 80% and 20% level contributions, respectively.
Fig. 4
Fig. 4. CoMSIA StDev*Coeff contour plots for HepG2 compounds in combination of Cpd11. (A) The steric contour map, where the green and yellow contours represent 80% and 20% level contributions, respectively. (B) The hydrogen bond donor contour map, where the cyan and purple contours represent 80% and 20% level contributions, respectively.
Fig. 5
Fig. 5. CoMFA StDev*Coeff contour plots for HCT-116 compounds in combination of Cpd11. (A) The steric contour map, where the green and yellow contours represent 70% and 30% level contributions, respectively. (B) The electrostatic contour map, where the blue and red contours represent 80% and 20% level contributions, respectively.
Fig. 6
Fig. 6. CoMSIA StDev*Coeff contour plots for HCT-116 compounds in combination of Cpd11. (A) The electrostatic contour map, where the blue and red contours represent 80% and 20% level contributions, respectively. (B) The hydrogen bond donor contour map, where the cyan and purple contours represent 80% and 20% level contributions, respectively.
Fig. 7
Fig. 7. CoMFA StDev*Coeff contour plots for MCF-7 compounds in combination of Cpd11. (A) The steric contour map, where the green and yellow contours represent 70% and 30% level contributions, respectively. (B) The electrostatic contour map, where the blue and red contours represent 80% and 20% level contributions, respectively.
Fig. 8
Fig. 8. CoMSIA StDev*Coeff contour plots for MCF-7 compounds in combination of Cpd11. (A) The electrostatic contour map, where the blue and red contours represent 80% and 20% level contributions, respectively. (B) The hydrogen bond donor contour map, where the cyan and purple contours represent 80% and 20% level contributions, respectively.
Fig. 9
Fig. 9. Re-docking pose and the crystal ligand (cyan = docked, green = original).
Fig. 10
Fig. 10. (A) The residues in VEGFR-2 active site around Cpd11. (B) The enlargement for Cpd11 in the binding site, which is displayed in stick, hydrogen bonds are shown as dotted black lines, and the nonpolar hydrogens were removed for clarity.
Fig. 11
Fig. 11. (A) The residues in VEGFR-2 active site around Cpd15. (B) The enlargement for Cpd15 in the binding site, which is displayed in stick, hydrogen bonds are shown as dotted black lines, and the nonpolar hydrogens were removed for clarity.
Fig. 12
Fig. 12. The RMSD of the backbone atoms relative to the docking structures as function of time. (A) The three replicates of VEGFR-2/Cpd11. (B) The three replicates of VEGFR-2/Cpd15.
Fig. 13
Fig. 13. Secondary structures as a function of time for VEGFR-2-Cpd11 and VEGFR-2-Cpd15.
Fig. 14
Fig. 14. The RMSF plot of the protein two MD systems (residue number are ranging from 1 to 310). Replicate trajectories of the same system are combined.
Fig. 15
Fig. 15. Per residue average energy contributions to binding free energy.
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