Structure-Based Virtual Screening, Molecular Dynamics and Binding Free Energy Calculations of Hit Candidates as ALK-5 Inhibitors.

Sheila C Araujo,Leonardo L G Ferreira,Kathia M Honorio,Michell O Almeida,Adriano D Andricopulo,Vinicius G Maltarollo

doi:10.3390/molecules25020264

Abstract

Activin-like kinase 5 (ALK-5) is involved in the physiopathology of several conditions, such as pancreatic carcinoma, cervical cancer and liver hepatoma. Cellular events that are landmarks of tumorigenesis, such as loss of cell polarity and acquisition of motile properties and mesenchymal phenotype, are associated to deregulated ALK-5 signaling. ALK-5 inhibitors, such as SB505154, GW6604, SD208, and LY2157299, have recently been reported to inhibit ALK-5 autophosphorylation and induce the transcription of matrix genes. Due to their ability to impair cell migration, invasion and metastasis, ALK-5 inhibitors have been explored as worthwhile hits as anticancer agents. This work reports the development of a structure-based virtual screening (SBVS) protocol aimed to prospect promising hits for further studies as novel ALK-5 inhibitors. From a lead-like subset of purchasable compounds, five molecules were identified as putative ALK-5 inhibitors. In addition, molecular dynamics and binding free energy calculations combined with pharmacokinetics and toxicity profiling demonstrated the suitability of these compounds to be further investigated as novel ALK-5 inhibitors.

Highlights

Cancer is associated to genetic mutations that provide specific characteristics to the affected cells, such as high levels of proliferation, metastasis, and evasion of apoptosis
From the redocking and cross-docking results displayed in Figure 2, we observe that the algorithm and, all parameters successfully reproduced the crystallographic conformation of the ligand and the main interactions at the binding site of Activin-like kinase 5 (ALK-5)
The poses of the hit compounds obtained during the structure-based virtual screening (SBVS) protocol were ranked according to the docking algorithmsability to find the compound pose with the lowest force field values, including scoring functions based on van der

Summary

Introduction

Cancer is associated to genetic mutations that provide specific characteristics to the affected cells, such as high levels of proliferation, metastasis, and evasion of apoptosis. (ALK-5), known as TGF-beta type I receptor (TGFβRI), is a transmembrane receptor involved in the development of various types of malignancies, such as pancreatic carcinoma, cervical cancer, and liver hepatoma [1,2,3,4,5]. TGFβ is a multipurpose cytokine that affects biological processes as regulation of cell proliferation and differentiation, immune response, angiogenesis and apoptosis. The complex function of TGFβ depends on the activation of two highly conserved single transmembrane serine/threonine kinases: type I (TGFβRI or ALK-5) and type II (TGFβRII) receptors. The mechanism of TGF-β activation involves the following steps: TGFβRII phosphorylates threonine residues in the GS (repeated series of glycine-serine) domain of ligand-occupied ALK-5 that occurs in the portion localized outside the membrane [10,11].

Methods

Results

Conclusion