Title:Pharmacophore-Based 3D-QSAR Modeling, Virtual Screening and Molecular Docking Analysis for the Detection of MERTK Inhibitors with Novel Scaffold
Volume: 19
Issue: 1
Author(s): Suwen Zhou, Lu Zhou, Ruguo Cui, Yahui Tian, Xiaoli Li, Rong You and Liangliang Zhong
Affiliation:
Keywords:
MERTK inhibitors, pharmacophore, 3D-QSAR, virtual screening, molecular docking, ADME.
Abstract: MERTK plays an important role in cell biology and is correlated with many cancers, such
as mantle cell lymphomas, pituitary adenomas, and T-cell acute lympholoblastic leukemia. So
identification of new MERTK inhibitors is of extreme importance. In this study, 107 MERTK
inhibitors with known activities were gathered to generate a ligand-based pharmacophore model
(ADDHH.4), followed by building a 3D-QSAR model, which had high value of coefficient of
determination (R2=0.9061) and high value of coefficient of determination (Q2=0.7442). For the
pharmacophore model, two hydrogen bond donors (D), one hydrogen bond receptor (A), and two
hydrophobic groups (H) were considered as the key elements contributing to ligand activity. The
model then served to search a drug-like database with 1.5 million molecules, and 47832 hits were obtained. Subsequently,
docking procedure was applied on these hits, and 840 compounds were obtained through high-throughput virtual
screening (HTVS). Standard precision (SP), extra precision (XP) and rule of five were also used in virtual screening
protocol. Finally, six candidates were identified as potential MERTK inhibitors, with the docking mode in MERTK
analyzed.
