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Virtual screening of small molecules databases for discovery of novel PARP-1 inhibitors: combination of in silico and in vitro studies.
J Biomol Struct Dyn. 2017 Jul; 35(9):1899-1915.JB

Abstract

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 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.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Ekhteiari Salmas R
a Department of Biophysics, School of Medicine , Bahcesehir University , Istanbul , Turkey.
Unlu A
b Faculty of Medicine, Department of Biophysics , Trakya University , Edirne , Turkey.
Bektaş M
c Istanbul Faculty of Medicine, Department of Biophysics , Istanbul University , Istanbul , Turkey.
Yurtsever M
d Department of Chemistry , Istanbul Technical University , Istanbul , Turkey.
Mestanoglu M
e School of Medicine , Bahcesehir University , Istanbul , Turkey.
Durdagi S
a Department of Biophysics, School of Medicine , Bahcesehir University , Istanbul , Turkey.

MeSH

Computer SimulationEnzyme InhibitorsHigh-Throughput Screening AssaysHumansIn Vitro TechniquesLigandsMolecular Docking SimulationMolecular Dynamics SimulationPoly (ADP-Ribose) Polymerase-1Protein BindingSmall Molecule LibrariesUser-Computer Interface

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27315035

Citation

Ekhteiari Salmas, Ramin, et al. "Virtual Screening of Small Molecules Databases for Discovery of Novel PARP-1 Inhibitors: Combination of in Silico and in Vitro Studies." Journal of Biomolecular Structure & Dynamics, vol. 35, no. 9, 2017, pp. 1899-1915.
Ekhteiari Salmas R, Unlu A, Bektaş M, et al. Virtual screening of small molecules databases for discovery of novel PARP-1 inhibitors: combination of in silico and in vitro studies. J Biomol Struct Dyn. 2017;35(9):1899-1915.
Ekhteiari Salmas, R., Unlu, A., Bektaş, M., Yurtsever, M., Mestanoglu, M., & Durdagi, S. (2017). Virtual screening of small molecules databases for discovery of novel PARP-1 inhibitors: combination of in silico and in vitro studies. Journal of Biomolecular Structure & Dynamics, 35(9), 1899-1915. https://doi.org/10.1080/07391102.2016.1199328
Ekhteiari Salmas R, et al. Virtual Screening of Small Molecules Databases for Discovery of Novel PARP-1 Inhibitors: Combination of in Silico and in Vitro Studies. J Biomol Struct Dyn. 2017;35(9):1899-1915. PubMed PMID: 27315035.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Virtual screening of small molecules databases for discovery of novel PARP-1 inhibitors: combination of in silico and in vitro studies. AU - Ekhteiari Salmas,Ramin, AU - Unlu,Ayhan, AU - Bektaş,Muhammet, AU - Yurtsever,Mine, AU - Mestanoglu,Mert, AU - Durdagi,Serdar, Y1 - 2016/07/17/ PY - 2016/6/18/pubmed PY - 2018/3/16/medline PY - 2016/6/18/entrez KW - E-pharmacophore KW - MM-PBSA KW - PARP-1 KW - QM-polarized ligand docking KW - free energy perturbation calculations KW - high-throughput virtual screening KW - in vitro colorimetric assay KW - molecular docking simulations KW - molecular dynamics (MD) simulations SP - 1899 EP - 1915 JF - Journal of biomolecular structure & dynamics JO - J Biomol Struct Dyn VL - 35 IS - 9 N2 - 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 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. SN - 1538-0254 UR - https://www.unboundmedicine.com/medline/citation/27315035/Virtual_screening_of_small_molecules_databases_for_discovery_of_novel_PARP_1_inhibitors:_combination_of_in_silico_and_in_vitro_studies_ DB - PRIME DP - Unbound Medicine ER -