Title:Anticancer Activity of Novel 1,3,4-oxadiazole Derivatives against PARP-1
Inhibitors: An In-silico Approach
Volume: 20
Issue: 4
Author(s): Praveen Kumar Patel, Preeya Negi, Sowmiya Arun, Kaviarasan Lakshmanan, Gowramma Byran*, Kalirajan Rajagopal and Gomathi Swaminathan
Affiliation:
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research,
Ooty, The Nilgiris, Tamil Nādu, India
Keywords:
PARP-1, cancer, 1, 3, 4-Oxadiazole, molecular docking, molecular dynamics simulation and anti-cancer.
Abstract:
Background: 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.
Objective: 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.
Methods: 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.
Results: 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.
Conclusion: 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.
