In-Silico Design of Phthalazine Derivatives as VEGFR-2 ‎Inhibitors: Molecular Docking and Pharmacological Profile ‎Studies

According to the world health organization (WHO) reports, cancer is thought to be the condition that causes the most fatalities after coronary disease, and by 2030, thirteen million deaths are anticipated to be recorded. In this research, molecular docking approach was utilized in designing more potent phthalazine derivatives as VEGFR-2 inhibitors. The pharmacological properties of the designed compounds were predicted to avoid drug failure after production. Before the start of the process, the docking protocol of the algorithm utilized in this work was validated by redocking the co-crystallized ligand (Sorafenib) with the initial VEGFR-2 binding site. The root mean square deviation (RMSD) score computed between the superimposed complexes of initial and redocked poses of Sorafenib was found to be 1.03Å. Moreover, the binding affinities of Sorafenib (MolDock score = -144.289 Kcal/mol, Re-rank score = -113.368 Kcal/mol) were utilized as a yardstick for the adoption of lead molecules among which compounds 21 and 22 with binding affinities of -146.77, and -151.651 Kcal/mol MolDock scores and -115.096, and -115.757 Kcal/mol Re-rank scores exceeding that of Sorafenib were explored. Compound 22 was utilized as a design template from which five hypothetical compounds with binding affinities ranging from -159.014 to -169.245 Kcal/mol MolDock scores and -121.591 to -134.697 Kcal/mol Re-rank scores were designed via the introduction of electron releasing groups to the ortho- and meta-positions of the p-chlorophenyl group. Pharmacological profiling leads to the affirmation of the designed inhibitors as potential drug candidates with welcoming ADMET properties with no serious toxicity challenges.