Experimental, Theoretical,\nand <i>In Silico</i> Studies of Potential CDC7 Kinase Inhibitors

In this work, we present the synthesis, solid-state characterization,\nand <i>in silico</i> studies of two pyrazole derivatives:\n5-(2-methylphenoxy)-3-methyl-1-phenyl-1<i>H</i>-pyrazole-4-carbaldehyde\n(I) and 5-(4-methylphenoxy)-3-methyl-1-phenyl-1<i>H</i>-pyrazole-4-carbaldehyde\n(II). The molecular crystal properties, in terms of intermolecular\nhydrogen bonds and other weak interactions, are analyzed using single\ncrystal X-ray diffraction. The Hirshfeld surfaces computational method\nis used to quantify the intermolecular interactions, density functional\ntheory for theoretical structural optimization, and its comparison\nwith the experimental structure and <i>in-silico</i> studies\nusing docking and molecular dynamics studies of I and II with CDC7-kinase.\nIn addition, the quantum theory of atoms in molecules (QTAIM) approach\nis applied to calculate the topological properties of electron density\nand the Laplacian of electron density of the chemical bonds of both\nmolecules. Compounds I and II crystallize in a monoclinic crystal\nsystem, and molecules are connected via C–H···O\nintermolecular hydrogen bonds. Hirshfeld surfaces analysis revealed\nthat the H···H type intercontact contributes more toward\nthe crystal packing. DFT-optimized structures show a perfect overlay\nwith the experimental structures. The <i>in silico</i> results\nshow that both I (−41.50 kcal/mol) and II (−44.53 kcal/mol)\nexhibit strong binding free energies as ligands binding to the active\nsites of the CDC7-kinase. The most significant contributions for ligand\nand protein binding in both compounds are dominated by van der Waals\ninteractions.