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.

• Klíčová slova
• PRR, TLR4, adjuvants, innate immunity, molecular dynamics, virtual screening,
• MeSH
• adjuvancia imunologická chemie   metabolismus   farmakologie   MeSH
• CHO buňky MeSH
• Cricetulus MeSH
• inhibiční koncentrace 50 MeSH
• interleukin-6 krev   MeSH
• lidé MeSH
• ligandy MeSH
• počítačová simulace MeSH
• povrchová plasmonová rezonance MeSH
• rychlé screeningové testy metody   MeSH
• simulace molekulární dynamiky MeSH
• simulace molekulového dockingu MeSH
• toll-like receptor 4 agonisté   metabolismus   MeSH
• tryptaminy chemie   MeSH
• vakcíny MeSH
• vazebná místa MeSH
• vztahy mezi strukturou a aktivitou * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adjuvancia imunologická MeSH
• IL6 protein, human MeSH Prohlížeč
• interleukin-6 MeSH
• ligandy MeSH
• TLR4 protein, human MeSH Prohlížeč
• toll-like receptor 4 MeSH
• tryptamine MeSH Prohlížeč
• tryptaminy MeSH
• vakcíny MeSH