Integrated support vector machine and pharmacophore based virtual screening driven identification of thiophene carboxamide scaffold containing compound as potential PARP1 inhibitor

• Published in: Journal of biomolecular structure & dynamics 2022-11, Vol.40 (18), p.8494-8507
• Main Authors: Singh, Maninder, Rajawat, Jyotika, Kuldeep, Jitendra, Shukla, Nidhi, Mishra, Durga Prasad, Siddiqi, Mohammad Imran
• Format: Article
• Language: English
• Subjects: molecular docking; PARP1; pharmacophore model; support vector machine; virtual screening
• ISSN: 0739-1102; 1538-0254
• DOI: 10.1080/07391102.2021.1913229

Poly (ADP-ribose) polymerase-1 (PARP1) inhibition strategy for cancer treatment is gaining advantage particularly in patients having a mutation in BRCA1/BRCA2 gene. To date, four drugs have obtained FDA approval and some inhibitors are in clinical trials. To identify more potent PARP1 inhibitors extensive research is going on to enrich the library of PARP1 inhibitors with compounds belonging to different classes. We employed an integrated virtual screening approach to identify potential PARP1 inhibitors. The sequential support vector machine (SVM) and pharmacophore model based virtual screening was carried out on the Maybridge library. The obtained hits were docked in the binding site of the PARP1 catalytic domain and nine drug-like compounds showing good ADME properties and form critical molecular interactions with the binding site residues were considered for the in vitro PARP1 inhibition assay. MD simulations were performed to decipher the stability of the PARP1-ligand complexes. Hydrogen bond interactions were also probed for their stability during MD simulations. We have identified three compounds (BTB02767, GK01172, and KM09200) showing 50% inhibition of PARP1 enzyme activity at 25 μM. BTB02767 and KM09200 have phthalazinone scaffold, while GK01172 bears a thiophene carboxamide scaffold, which could be a new chemotype of PARP1 inhibitors. In conclusion, GK01172 may serve as an important compound for further development of PARP1 inhibitors containing thiophene carboxamide scaffold. Communicated by Ramaswamy H. Sarma