A Structural and In Silico Investigation of Potential CDC7 Kinase Enzyme Inhibitors

Mohanbabu Mookkan; Saravanan Kandasamy; Abdel-Basit Al-Odayni; Naaser Ahmed Yaseen Abduh; Sugarthi Srinivasan; Bistuvalli Chandrashekara Revannasidappa; Vasantha Kumar; Kalaiarasi Chinnasamy; Sanmargam Aravindhan; Madan Kumar Shankar

doi:10.1021/acsomega.3c07059

A Structural and In Silico Investigation of Potential CDC7 Kinase Enzyme Inhibitors

ACS Omega. 2023 Nov 27;8(49):47187-47200. doi: 10.1021/acsomega.3c07059. eCollection 2023 Dec 12.

Affiliations

¹ Department of Physics, Presidency College (Autonomous), University of Madras, Chennai 600 005, India.
² Faculty of Chemistry, University of Warsaw, Ludwika Pasteura 1, Warsaw 02-093, Poland.
³ Department of Restorative Dental Science, College of Dentistry, King Saud University, P.O. Box 60169, Riyadh 11545, Saudi Arabia.
⁴ Department of Chemistry, College of Science, King Saud University, P.O. Box 2455, Riyadh 11451, Saudi Arabia.
⁵ Department of Physics and Nanotechnology, SRM Institute of Science and Technology, Kattankulathur 603203, India.
⁶ Department of Pharmaceutical Chemistry, NGSM Institute of Pharmaceutical Sciences of Nitte - Deemed to be University, Paneer, Deralakatte, Mangalore 575018, Karnataka India.
⁷ Department of P.G. Chemistry, Sri Dharmasthala Manjunatheshwara College (Autonomous), Ujire 574240, India.
⁸ Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560 012, India.
⁹ Department of Chemistry-BMC, University of Uppsala, Husargatan 3, Uppsala 75237, Sweden.

Abstract

A crucial role in the regulation of DNA replication is played by the highly conserved CDC kinase. The CDC7 kinase could serve as a target for therapeutic intervention in cancer. The primary heterocyclic substance is pyrazole, and its derivatives offer great potential as treatments for cancer cell lines. Here, we synthesized the two pyrazole derivatives: 4-(2-(4-chlorophenyl)hydrazinyl)-5-methyl-2-tosyl-1H-pyrazol-3(2H)-one (PYRA-1) and 4-(2-(2,4-difluorophenyl)hydrazinyl)-5-methyl-2-tosyl-1H-pyrazol-3(2H)-one (PYRA-2). The structural confirmation of both the compounds at the three-dimensional level is characterized using single crystal X-ray diffraction and density functional theory. Furthermore, the in silico chemical biological properties were derived using molecular docking and molecular dynamics (MD) simulations. PYRA-1 and PYRA-2 crystallize in the P-1 (a = 8.184(9), b = 14.251(13), c = 15.601(15), α = 91.57(8), β = 97.48(9), 92.67(9), V = 1801.1(3) 3, and Z = 2) and P2₁/n (a = 14.8648(8), b = 8.5998(4), c = 15.5586(8), β = 116.47(7), V = 1780.4(19) 3, and Z = 4), space groups, respectively. In both PYRA-1 and PYRA-2 compounds, C-H···O intermolecular connections are common to stabilize the crystal structure. In addition, short intermolecular interactions stabilizes with C-H···π and π-π stacking. Crystal packing analysis was quantified using Hirshfeld surface analysis resulting in C···H, O···H, and H···H contacts in PYRA-1 exhibiting more contribution than in PYRA-2. The conformational stabilities of the molecules are same in the gas and liquid phases (water and DMSO). The docking scores measured for PYRA-1 and PYRA-2 with CDC7 kinase complexes are -5.421 and -5.884 kcal/mol, respectively. The MD simulations show that PYRA-2 is a more potential inhibitor than PYRA-1 against CDC7 kinase.