Molecular modelling studies for 4-oxo-1,4-dihydroquinoline-3-carboxamide derivatives as anticancer agents

The ligand library reporting anticancer activities was taken from literature containing forty-two 4-oxo-1,4-dihydroquinoline-3-carboxamides derivatives and was thoroughly investigated against cancer target (pdb id-5U6B) using docking protocol. In order to design future analogues, we carried out our research to develop the Atom based- and Field based-3D QSAR (Quantitative structure–activity relationship models) models.PHASE was employed for the common pharmacophore generation and 3D-QSAR studies. The protein target (pdb id-5U6B) was selected and docking was used in order to check better binding modes between target and ligands. The crystal structure of Axl kinase domain in complex with a macrocyclic inhibitor complex (pdb id-5U6B) had a resolution of 2.84 Å. The free energy was calculated by using PRIME-Molecular mechanics with generalized Born and surface area solvation (MM/GBSA). The molecular properties and ADME parameter were calculated using Qikprop utility.Out of 12 developed pharmacophore hypothesis using the PHASE module, a six point AAHRRR_1 hypothesis found best with good scoring parameters involving the two acceptor features, one hydrophobic feature and three ring features. For the atom based-3D QSAR model, a good cross-validation correlation coefficient i.e. Q2 value as 0.5715 for test set and R2 (a correlation coefficient) as 0.8704 for training set molecules. In case of field based QSAR, a cross-validation correlation coefficient (Q2) for test set as 0.5697 and R2 (a correlation coefficient) as 0.817 for training set molecules. Both the models show good statistical significance for future designing. The compound 9L observed as best docked for target 5U6B having docking score of −4.085 kcal/mol and PRIME MM/GBSA (Prime/Molecular Mechanics Generalized Born Surface Area) dg bind energy as-63.302 kcal/mol. The values for rule of five for all dataset compounds were found within range. Percentage human oral absorption values were also >80% except few compounds. Finally, our current study will helpful for researchers in order to develop new 4-oxo-1,4-dihydroquinoline-3-carboxamides derivatives as more potent anticancer agents. Keywords: Pharmacophore model, Anticancer agents, Virtual screening, Molecular docking