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Molecules 2018, 23(1), 102; doi:10.3390/molecules23010102

Rational Design of a New Class of Toll-Like Receptor 4 (TLR4) Tryptamine Related Agonists by Means of the Structure- and Ligand-Based Virtual Screening for Vaccine Adjuvant Discovery

1
Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 50005 Hradec Kralove, Czech Republic
2
Department of Forensic Medicine and Intensive Medicine, Faculty of Medicine, University of Ostrava, Syllabova 19, Ostrava 70300, Czech Republic
3
Department of Chemistry, Faculty of Science, University of Hradec Kralove, Rokitanskeho 62, 50003 Hradec Kralove, Czech Republic
4
Center for Basic and Applied Research, Faculty of Informatics and Management, University of Hradec Kralove, Rokitanskeho 62, 50003 Hradec Kralove, Czech Republic
5
Laboratory of Molecular Modeling Applied to Chemical and Biological Defense, Military Institute of Engineering, Praca General Tiburcio 80, Rio de Janeiro 22290-270, Brazil
*
Author to whom correspondence should be addressed.
Received: 18 December 2017 / Revised: 28 December 2017 / Accepted: 29 December 2017 / Published: 4 January 2018
(This article belongs to the Section Medicinal Chemistry)
View Full-Text   |   Download PDF [2731 KB, uploaded 4 January 2018]   |  

Abstract

In order to identify novel lead structures for human toll-like receptor 4 (hTLR4) modulation virtual high throughput screening by a peta-flops-scale supercomputer has been performed. Based on the in silico studies, a series of 12 compounds related to tryptamine was rationally designed to retain suitable molecular geometry for interaction with the hTLR4 binding site as well as to satisfy general principles of drug-likeness. The proposed compounds were synthesized, and tested by in vitro and ex vivo experiments, which revealed that several of them are capable to stimulate hTLR4 in vitro up to 25% activity of Monophosphoryl lipid A. The specific affinity of the in vitro most potent substance was confirmed by surface plasmon resonance direct-binding experiments. Moreover, two compounds from the series show also significant ability to elicit production of interleukin 6. View Full-Text
Keywords: PRR; TLR4; innate immunity; virtual screening; molecular dynamics; adjuvants PRR; TLR4; innate immunity; virtual screening; molecular dynamics; adjuvants
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Honegr, J.; Dolezal, R.; Malinak, D.; Benkova, M.; Soukup, O.; Almeida, J.S.F.D.; Franca, T.C.C.; Kuca, K.; Prymula, R. Rational Design of a New Class of Toll-Like Receptor 4 (TLR4) Tryptamine Related Agonists by Means of the Structure- and Ligand-Based Virtual Screening for Vaccine Adjuvant Discovery. Molecules 2018, 23, 102.

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