In Silico Design and Selection of New Tetrahydroisoquinoline-Based CD44 Antagonist Candidates.

Angel J Ruiz-Moreno,Marco A Velasco-Velázquez,Alexander Dömling,Atilio Reyes-Romero

doi:10.3390/molecules26071877

Abstract

CD44 promotes metastasis, chemoresistance, and stemness in different types of cancer and is a target for the development of new anti-cancer therapies. All CD44 isoforms share a common N-terminal domain that binds to hyaluronic acid (HA). Herein, we used a computational approach to design new potential CD44 antagonists and evaluate their target-binding ability. By analyzing 30 crystal structures of the HA-binding domain (CD44HAbd), we characterized a subdomain that binds to 1,2,3,4-tetrahydroisoquinoline (THQ)-containing compounds and is adjacent to residues essential for HA interaction. By computational combinatorial chemistry (CCC), we designed 168,190 molecules and compared their conformers to a pharmacophore containing the key features of the crystallographic THQ binding mode. Approximately 0.01% of the compounds matched the pharmacophore and were analyzed by computational docking and molecular dynamics (MD). We identified two compounds, Can125 and Can159, that bound to human CD44HAbd (hCD44HAbd) in explicit-solvent MD simulations and therefore may elicit CD44 blockage. These compounds can be easily synthesized by multicomponent reactions for activity testing and their binding mode, reported here, could be helpful in the design of more potent CD44 antagonists.

Highlights

CD44 is a transmembrane glycoprotein that functions as a receptor for the glycosaminoglycan hyaluronic acid (HA), an integral component of the extracellular matrix [1,2]
We identified that small molecules sharing a 1,2,3,4-tetrahydroiso quinoline (THQ) motif are frequently co-crystallized with CD44HAbd in a subdomain adjacent to the residues that are essential for HA-binding
The three human structures correspond to the apo form of CD44HAbd

Summary

Introduction

CD44 is a transmembrane glycoprotein that functions as a receptor for the glycosaminoglycan hyaluronic acid (HA), an integral component of the extracellular matrix [1,2]. CD44 is expressed on multiple cells, including embryonic stem cells and differentiated cells, mediating cellular functions such as adhesion, homing, migration, and extravasation [1,2]. CD44 activation by HA in cancer cells induces transcriptional and epigenetic changes that stimulate signaling pathways controlling invasiveness and metastasis, chemoresistance, and stemness [9,10,11]. In breast cancer cells, HA binding to CD44 induces epithelial–mesenchymal transition, which increases cell migration and invasive capacity [12], and promotes survival under detached conditions during the development of metastasis [13]. CD44 is expressed in cancer stem cells that survive chemotherapy in models of glioblastoma [14], breast [15], pancreatic [16], colorectal [17], and prostate [18] cancer. Blockage of HA-binding to CD44 has been proposed as a potential therapeutic strategy for cancer

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Results

Conclusion