Virtual screening of small molecules databases for discovery of novel PARP-1 inhibitors: combination of in silico and in vitro studies.
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 IC50values of 0.56 and 63 μM 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.
a Department of Biophysics, School of Medicine , Bahcesehir University , Istanbul , Turkey.
Ramin
R
Ekhteiari Salmas
b Faculty of Medicine, Department of Biophysics , Trakya University , Edirne , Turkey.
Ayhan
A
Unlu
c Istanbul Faculty of Medicine, Department of Biophysics , Istanbul University , Istanbul , Turkey.
Muhammet
M
Bektaş
d Department of Chemistry , Istanbul Technical University , Istanbul , Turkey.
Mine
M
Yurtsever
e School of Medicine , Bahcesehir University , Istanbul , Turkey.
Mert
M
Mestanoglu
a Department of Biophysics, School of Medicine , Bahcesehir University , Istanbul , Turkey.
Serdar
S
Durdagi
D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D057166:High-Throughput Screening Assays; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000037:antagonists & inhibitors / Q000737:chemistry*; D011485:Protein Binding; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology; D014584:User-Computer Interface
D004791:Enzyme Inhibitors; D008024:Ligands; D054852:Small Molecule Libraries; D000071137:Poly (ADP-Ribose) Polymerase-1
E-pharmacophore; MM-PBSA; PARP-1; QM-polarized ligand docking; free energy perturbation calculations; high-throughput virtual screening; in vitro colorimetric assay; molecular docking simulations; molecular dynamics (MD) simulations