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

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