Discovery of novel aminopiperidinyl amide CXCR4 modulators through virtual screening and rational drug design

• Type of Material: Article
• Authors: Yoon Hyeun Oum, Emory University; Steven A Kell, Emory University; Younghyoun Yoon, Emory University; Zhongxing Liang, Emory University; Pieter Burger, Emory University; Hyunsuk Shim, Emory University
• Language: English
• Date: 2020-09-01
• Publisher: ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2020 Elsevier Masson SAS. All rights reserved.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.ejmech.2020.112479
• Title of Journal or Parent Work: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
• Volume: 201
• Start Page: 112479
• End Page: 112479
• Grant/Funding Information: This work was partially supported by NIH grant U01EB028145.
• Keywords: AMD3100; Pharmacology & Pharmacy; SMALL-MOLECULE; DOCKING; INHIBITORS; Structure-based drug design; BINDING; Molecular docking; Chemistry, Medicinal; CHEMOKINE RECEPTOR CXCR4; C-X-C chemokine receptor type 4 (CXCR4); Ligand shape similarity; Life Sciences & Biomedicine; IDENTIFICATION; Chemokine modulator; HIV-1; Molecular dynamics; Science & Technology; POTENT; BICYCLAM NONPEPTIDE ANTAGONISTS

Abstract

The C-X-C chemokine receptor type 4 (CXCR4) is a potential therapeutic target for HIV infection, metastatic cancer, and inflammatory autoimmune diseases. In this study, we screened the ZINC chemical database for novel CXCR4 modulators through a series of in silico guided processes. After evaluating the screened compounds for their binding affinities to CXCR4 and inhibitory activities against the chemoattractant CXCL12, we identified a hit compound (ZINC 72372983) showing 100 nM affinity and 69% chemotaxis inhibition at the same concentration (100 nM). To increase the potency of our hit compound, we explored the protein-ligand interactions at an atomic level using molecular dynamics simulation which enabled us to design and synthesize a novel compound (Z7R) with nanomolar affinity (IC50 = 1.25 nM) and improved chemotaxis inhibition (78.5%). Z7R displays promising anti-inflammatory activity (50%) in a mouse edema model by blocking CXCR4-expressed leukocytes, being supported by our immunohistochemistry study.