Computational investigation of TGF-β receptor inhibitors for treatment of idiopathic pulmonary fibrosis: Field-based QSAR model and molecular dynamics simulation

Wei Li; Xue Liu; Suleiman Muhammad; JiYue Shi; YanQiu Meng; Jian Wang

doi:10.1016/j.compbiolchem.2018.07.002

Computational investigation of TGF-β receptor inhibitors for treatment of idiopathic pulmonary fibrosis: Field-based QSAR model and molecular dynamics simulation

Comput Biol Chem. 2018 Oct:76:139-150. doi: 10.1016/j.compbiolchem.2018.07.002. Epub 2018 Jul 7.

Authors

Wei Li¹, Xue Liu¹, Suleiman Muhammad², JiYue Shi², YanQiu Meng³, Jian Wang⁴

Affiliations

¹ Department of Pharmaceutical Engineering, Shenyang University of Chemical Technology, Shenyang, China.
² Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China.
³ Department of Pharmaceutical Engineering, Shenyang University of Chemical Technology, Shenyang, China. Electronic address: mengyanqiu@hotmail.com.
⁴ Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, Shenyang 110016, China. Electronic address: jianwang@syphu.edu.cn.

PMID: 30015175
DOI: 10.1016/j.compbiolchem.2018.07.002

Abstract

The discovery of drugs relevant to transforming growth factor β (TGF-β) receptor inhibitors have been considered as a considerable challenge during therapy idiopathic pulmonary fibrosis diseases. For the first time, herein we illustrate a field-based quantitative structure-activity relationship (QSAR) model and molecular dynamics (MD) simulations for novel 7-substituted-pyrazolo [4, 3-b] pyridine derivatives with biological activity for the TGF-β receptor, with an attempt of elucidating the 3D structural features that are essential for the activity. Results demonstrate that the field-based model (Q² = 0.548, R²_training = 0.840, R²_test = 0.750) are acceptable with good predictive capabilities. In addition, MD studies were also carried out on the training set with the aim of exploring their binding modes in the active pocket of TGF-β receptor, resulting in some of the crucial structural fragments which are responsible for inhibitory activity. Therefore, we summarized the following features required for TGF-β receptor inhibition: electronegative in region1, bulky groups in region2 and smaller groups in region3. Based on the model and related information, we hope the above information provides an important insight for understanding the interactions of the inhibitors and TGF-β receptor, which may be useful in discovering novel potent inhibitors.

Keywords: Idiopathic pulmonary fibrosis; Molecular dynamics; Structure–activity relationships; TGF-β receptor.

MeSH terms

Binding Sites
Humans
Idiopathic Pulmonary Fibrosis / drug therapy*
Least-Squares Analysis
Ligands
Models, Chemical
Molecular Dynamics Simulation
Protein Binding
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / metabolism*
Protein Serine-Threonine Kinases / antagonists & inhibitors*
Protein Serine-Threonine Kinases / chemistry
Protein Serine-Threonine Kinases / metabolism*
Quantitative Structure-Activity Relationship
Receptor, Transforming Growth Factor-beta Type I
Receptors, Transforming Growth Factor beta / antagonists & inhibitors*
Receptors, Transforming Growth Factor beta / chemistry
Receptors, Transforming Growth Factor beta / metabolism*

Substances

Ligands
Protein Kinase Inhibitors
Receptors, Transforming Growth Factor beta
Protein Serine-Threonine Kinases
Receptor, Transforming Growth Factor-beta Type I