2. Academic Validation
  3. Design and development of benzoxazole derivatives with toll-like receptor 9 antagonism

Design and development of benzoxazole derivatives with toll-like receptor 9 antagonism

  • Eur J Med Chem. 2017 Jul 7:134:334-347. doi: 10.1016/j.ejmech.2017.03.086.
Swarnali Roy 1,  Ayan Mukherjee 2,  Barnali Paul 2,  Oindrila Rahaman 3,  Shounak Roy 3,  Gundaram Maithri 1,  Bandaru Ramya 3,  Sourav Pal 1,  Dipyaman Ganguly 4,  Arindam Talukdar 5
Affiliations

Affiliations

  • 1 Department of Organic and Medicinal Chemistry, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032, WB, India.
  • 2 Department of Organic and Medicinal Chemistry, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032, WB, India; Academy of Scientific and Innovative Research, Kolkata 700032, WB, India.
  • 3 Department of Cancer Biology and Inflammatory Disorders, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032 WB, India.
  • 4 Department of Cancer Biology and Inflammatory Disorders, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032 WB, India; Academy of Scientific and Innovative Research, Kolkata 700032, WB, India. Electronic address: dipyaman@iicb.res.in.
  • 5 Department of Organic and Medicinal Chemistry, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Kolkata 700032, WB, India; Academy of Scientific and Innovative Research, Kolkata 700032, WB, India. Electronic address: atalukdar@iicb.res.in.
PMID: 28437629 DOI: 10.1016/j.ejmech.2017.03.086
Abstract

Toll-like Receptor 9 (TLR9) is a major therapeutic target for numerous inflammatory disorders. Development of small molecule inhibitors for TLR9 remains largely empirical due to lack of structural understanding of potential TLR9 antagonism by small molecules and due to the unusual topology of the ligand binding surface of the receptor. To develop a structural model for rational design of small molecule TLR9 antagonists, an enhanced homology model of human TLR9 (hTLR9) was constructed. Binding mode analysis of a series of molecules having characteristic molecular geometry, flexibility and basicity was conducted based on crystal structure of the inhibitory DNA (iDNA) bound to horse and bovine TLR9. Interaction with specific amino acid residues in four leucine rich repeat (LRR) regions of TLR9 was identified to be critical for antagonism by small molecules. The biological validation of TLR9 antagonism and its correlation with probe-receptor interactions led to a reliable model that could be used for development of novel small molecules with potent TLR9 antagonism (IC50 30-100 nM) with excellent selectivity against TLR7.

Keywords

Antagonist; Computational analysis; Drug design; FGDQSWJQAISDMB-UHFFFAOYSA-N; Homology model; Inflammation; TLR7; TLR9.

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