药效团
生物信息学
虚拟筛选
聚ADP核糖聚合酶
对接(动物)
分子力学
体外
分子动力学
化学
计算生物学
小分子
聚合酶
酶
立体化学
数据库
计算化学
生物化学
生物
计算机科学
护理部
基因
医学
作者
Ramin Ekhteiari Salmas,Ayhan Ünlü,Muhammet Bektaş,Mine Yurtsever,Mert Mestanoğlu,Serdar Durdağı
标识
DOI:10.1080/07391102.2016.1199328
摘要
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.
科研通智能强力驱动
Strongly Powered by AbleSci AI