Design of some phthalazine molecules as novel VEGFR-2 target inhibitors through 3D-QSAR modeling, molecular docking and dynamic simulation and pharmacokinetics profiling

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AbstractBreast cancer is one of the dominant cause of cancer-related mortality in females, with an incidence of approximately 1.3 million cases annually, necessitating the development of effective therapeutic strategies. In this study, 3D-QSAR models were reported based on Phthalazine derivatives as VEGFR-2 inhibitors. The activities of these derivatives were correlated with the steric (S), electrostatic (E), hydrogen bond acceptor (A), and donor (D), and hydrophobic (H) fields, which served as critical parameters in model development. Statistical studies of these models showed that the best models are; CoMFA_S (Q2 = 0.623, R2 = 0.941), and CoMSIA_E + D (Q2 = 0.615, R2 = 0.977). Based on the insights from the model fields and docking simulation of the template (compound 17), twelve molecules were designed. These novel molecules exhibited stronger potency compared to the template and the standard, Sorafenib. Compound 17A emerged as the most potent, with pIC50 = 5.98, for CoMFA_S and 5.85, for CoMSIA_E + D, and a strong docking affinity of − 97.271 kcal/mol, therefore subjected to a 100-ns MD simulation. Results indicate better interaction and stabilizing potential over Sorafenib, due to the lower RMSD, RMSF, Rg, values and favorable hydrogen bond analyses. These conclusions were validated by Gibbs free energy analysis and MM-GBSA calculations, revealing a more favorable interaction free energy of − 18.48 kcal/mol related to Sorafenib. Furthermore, these designed compounds demonstrated promising pharmacokinetic profiles.