Virtual screening of small molecules databases for discovery of novel PARP-1 inhibitors: combination of in silico and in vitro studies

Salmas R. E., ÜNLÜ A., Bektas M., Yurtsever M., Mestanoglu M., DURDAĞI S.

JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS, cilt.35, sa.9, ss.1899-1915, 2017 (SCI-Expanded) identifier identifier identifier

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 35 Sayı: 9
  • Basım Tarihi: 2017
  • Doi Numarası: 10.1080/07391102.2016.1199328
  • Dergi Adı: JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Sayfa Sayıları: ss.1899-1915
  • Anahtar Kelimeler: PARP-1, molecular docking simulations, QM-polarized ligand docking, high-throughput virtual screening, MM-PBSA, molecular dynamics (MD) simulations, E-pharmacophore, free energy perturbation calculations, in vitro colorimetric assay, RESISTANCE-MODIFYING AGENTS, POLY(ADP-RIBOSE) POLYMERASE-1, BIOLOGICAL EVALUATION, DYNAMICS, DOCKING, DESIGN, IDENTIFICATION, BINDING, POTENT, OPTIMIZATION
  • İstanbul Üniversitesi Adresli: Evet

Özet

Poly(ADP-ribose) polymerase-1 (PARP-1) enzyme has critical roles in DNA replication repair and recombination. Thus, PARP-1 inhibitors play an important role in the cancer therapy. In the current study, we have performed combination of in silico and in vitro studies in order to discover novel inhibitors against PARP-1 target. Structure-based virtual screening was carried out for an available small molecules database. A total of 257,951 ligands from Otava database were screened at the binding pocket of PARP-1 using high-throughput virtual screening techniques. Filtered structures based on predicted binding energy results were then used in more sophisticated molecular docking simulations (i.e. Glide/standard precision, Glide/XP, induced fit docking - IFD, and quantum mechanics polarized ligand docking - QPLD). Potential high binding affinity compounds that are predicted by molecular simulations were then tested by in vitro methods. Computationally proposed compounds as PARP-1 inhibitors (Otava Compound Codes: 7111620047 and 7119980926) were confirmed by in vitro studies. In vitro results showed that compounds 7111620047 and 7119980926 have IC50 values of 0.56 and 63M against PARP-1 target, respectively. The molecular mechanism analysis, free energy perturbation calculations using long multiple molecular dynamics simulations for the discovered compounds which showed high binding affinity against PARP-1 enzyme, as well as structure-based pharmacophore development (E-pharmacophore) studies were also studied.