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.

Biomedical Research Centre University Hospital Hradec Kralove Sokolska 581 50005 Hradec Kralove Czech Republic

Center for Basic and Applied Research Faculty of Informatics and Management University of Hradec Kralove Rokitanskeho 62 50003 Hradec Kralove Czech Republic

Department of Chemistry Faculty of Science University of Hradec Kralove Rokitanskeho 62 50003 Hradec Kralove Czech Republic

Department of Forensic Medicine and Intensive Medicine Faculty of Medicine University of Ostrava Syllabova 19 Ostrava 70300 Czech Republic

Laboratory of Molecular Modeling Applied to Chemical and Biological Defense Military Institute of Engineering Praca General Tiburcio 80 Rio de Janeiro 22290 270 Brazil

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