Anticancer Activity of Novel 1,3,4-oxadiazole Derivatives against PARP-1 Inhibitors: An In-silico Approach

Abstract

Nuclear enzyme poly (ADP-ribose) polymerase-1 (PARP-1) controls the cell cycle, DNA repair, transcription, and replication processes. In this study, olaparib and rucaparib have been taken as standard drugs for comparison of results. As per previous research data, 1,3,4-Oxadiazole moiety has multidirectional biological activity and shows high activity against cancer. This study aimed to carry out the in silico ligand-based screening for the identification of hits for PARP1 inhibitors bearing 1,3,4-thiadiazole derivatives using Schrodinger suite 2022-1 and to perform MMGBSA and molecular dynamics simulation for lead molecules. A total of 32 derivatives of 1,3,4-Oxadiazole were designed with four different acids: phenoxy acetic acid, 1-Naphthoxy acetic acid, 2-Naphthoxy acetic acid, and piperonylic acid. Molecular docking (XP) studies were performed between 4ZZZ.pdb and the designed analogues, and the binding affinity values lay in the range of -8.52 to -3.52 kcal/mol. 2D interactions between the protein and the ligand were observed. Based on the binding affinity values and ADMET results, top 10 analogues were selected for performing MM-GBSA.A total of 32 derivatives of 1,3,4-Oxadiazole were designed with four different acids that are Phenoxy acetic acid, 1-Naphthoxy acetic acid, 2-Naphthoxy acetic acid, and Piperonylic acid. Molecular docking (XP) studies were performed between 4ZZZ.pdb and the designed analogues and the binding affinity values lie in the range of -8.52 to -3.52 kcal/mol. 2D interactions between the protein and the ligand are observed. Based on the binding affinity values and ADMET results top 10 analogues were selected for performing MM-GBSA. The dG-bind score of the top compounds varied from -2.30 to -60.67 kcal/mol, and analogue D4 was selected for MD simulation studies for 100ns. Results of Molecular dynamics (MD) studies showed that D4 interacted with amino acid residues, and the ligand-protein interaction stabilized from 58-90ns. The in silico study's findings suggested that the chemicals A1, A3, B1, B2, B3, B4, C1, C6, D1, and D4 might be significantly active against breast cancer with potential therapeutic benefits and are likely to be useful after further development. In conclusion, numerous molecules exhibit a high affinity for PARP-1 when derived from 1,3,4-oxadiazole. The in silico study's findings suggested that the chemicals A1, A3, B1, B2, B3, B4, C1, C6, D1, and D4 might be significantly active against breast cancer with potential therapeutic benefits and are likely to be useful after further development.