Abstract

DESIGN, SYNTHESIS AND MOLECULAR DOCKING OF VELIPARIB ANALOGUES AS POTENT PARP INHIBITORS FOR BREAST CANCER

Komal Bisht* and Dr. Praveen Kumar

ABSTRACT

Breast cancer is characterized by the uncontrolled growth of abnormal cells within the breast tissue, forming a lump or mass known as a tumor. PARP plays a crucial role in the maintenance of genomic stability by participating in the repair of DNA damage. When DNA in a cell is damaged, PARP is activated and helps initiate the repair process. Thus, PARP is a novel target for anticancer activity. Veliparib is a potent inhibitor of PARP and shows potent inhibition of breast cancer. Thus we design new 28 novel derivatives of veliparib and also design synthetic protocol to synthesize new 28 veliparib derivatives. In the presence of 3,6‐di(pyridin‐2‐yl)‐1,2,4,5‐tetrazine (PYTZ) and visible light, 2,3-diaminobenzamide undergoes a reaction with substituted 1H-indole-3-carbaldehyde, resulting in the formation of analogues of 2-(5,6-dimethyl-1H-indol-3-yl)-1H-benzo[d]imidazole-4-carboxamide. Thus these compounds also promise as inhibitors of PARP for breast cancer. Every one of the 28 analogs was examined utilizing "Lipinski's standard of five" and showed adequate boundaries: sub-atomic mass in the scope of 276.29 - 434.08 g/mol, hydrogen bond acceptors (HBA) in the scope of 2 - 4, hydrogen bond contributors (HBD) in the scope of 3 - 5, LogP in the scope of 1.25 - 3.38, and molar refractivity in the scope of 81.44 - 96.88. Our molecular docking identified several candidate molecules with promising binding affinities. Lower docking scores indicate stronger interactions between the molecules and their targets. Compound KVI 17 interacts with amino acid residues TYR896, TYR889, TYR907, ALA898, and LYS903 through hydrophobic bonding and GLY863 through hydrogen bonding, with a docking score of -10.0026 Kcal/Mol, similar to Veliparib. Compounds KVI 15 and KVI 21 exhibited interactions like KVI 17, excluding GLY863, with docking scores of -9.84101 and -9.84004 Kcal/Mol respectively. The compounds KVI 3, KVI 4 also KVI 10 showed slightly lower promising binding affinities as -9.73802, -9.74503 and -9.79441 Kcal/Mol respectively. The compounds KVI 8, KVI 23, and KVI 28 exhibited lower promising binding affinities, with dock scores of -8.64454, -8.53371, & -8.60667 Kcal/Mol respectively. Resting compounds showed moderate docking scores ranging from -8.80656 to -9.79441 Kcal/Mol. Therefore, these analogues may be purposed for advanced examination as PARP inhibitors to conflict breast cancer, ovarian cancer and PARP-associated cancer.

Keywords: Breast cancer, Ovarian cancer, PARP, PARP inhibitors, Veliparib derivatives, Lipinski's rule of five, Molecular docking.