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The crystal structures of human alpha-thrombin complexed with active site-directed diamino benzo[b]thiophene derivatives: a binding mode for a structurally novel class of inhibitors.
Protein Sci. 2000 Jan; 9(1):29-36.PS

Abstract

The crystal structures of four active site-directed thrombin inhibitors, 1-4, in a complex with human alpha-thrombin have been determined and refined at up to 2.0 A resolution using X-ray crystallography. These compounds belong to a structurally novel family of inhibitors based on a 2,3-disubstituted benzo[b]thiophene structure. Compared to traditional active-site directed inhibitors, the X-ray crystal structures of these complexes reveal a novel binding mode. Unexpectedly, the lipophilic benzo[b]thiophene nucleus of the inhibitor appears to bind in the S1 specificity pocket. At the same time, the basic amine of the C-3 side chain of the inhibitor interacts with the mostly hydrophobic proximal, S2, and distal, S3, binding sites. The second, basic amine side chain at C-2 was found to point away from the active site, occupying a location between the S1 and S1' sites. Together, the aromatic rings of the C-2 and C-3 side chains sandwich the indole ring of Trp60D contained in the thrombin S2 insertion loop defined by the sequence "Tyr-Pro-Pro-Trp." [The thrombin residue numbering used in this study is equivalent to that reported for chymotrypsinogen (Hartley BS, Shotton DM, 1971, The enzymes, vol. 3. New York: Academic Press. pp 323-373).] In contrast to the binding mode of more classical thrombin inhibitors (D-Phe-Pro-Arg-H, NAPAP, Argatroban), this novel class of benzo[b]thiophene derivatives does not engage in hydrogen bond formation with Gly216 of the thrombin active site. A detailed analysis of the three-dimensional structures not only provides a clearer understanding of the interaction of these agents with thrombin, but forms a foundation for rational structure-based drug design. The use of the data from this study has led to the design of derivatives that are up to 2,900-fold more potent than the screening hit 1.

Authors+Show Affiliations

Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. nyc@lilly.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

10739244

Citation

Chirgadze, N Y., et al. "The Crystal Structures of Human Alpha-thrombin Complexed With Active Site-directed Diamino Benzo[b]thiophene Derivatives: a Binding Mode for a Structurally Novel Class of Inhibitors." Protein Science : a Publication of the Protein Society, vol. 9, no. 1, 2000, pp. 29-36.
Chirgadze NY, Sall DJ, Briggs SL, et al. The crystal structures of human alpha-thrombin complexed with active site-directed diamino benzo[b]thiophene derivatives: a binding mode for a structurally novel class of inhibitors. Protein Sci. 2000;9(1):29-36.
Chirgadze, N. Y., Sall, D. J., Briggs, S. L., Clawson, D. K., Zhang, M., Smith, G. F., & Schevitz, R. W. (2000). The crystal structures of human alpha-thrombin complexed with active site-directed diamino benzo[b]thiophene derivatives: a binding mode for a structurally novel class of inhibitors. Protein Science : a Publication of the Protein Society, 9(1), 29-36.
Chirgadze NY, et al. The Crystal Structures of Human Alpha-thrombin Complexed With Active Site-directed Diamino Benzo[b]thiophene Derivatives: a Binding Mode for a Structurally Novel Class of Inhibitors. Protein Sci. 2000;9(1):29-36. PubMed PMID: 10739244.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The crystal structures of human alpha-thrombin complexed with active site-directed diamino benzo[b]thiophene derivatives: a binding mode for a structurally novel class of inhibitors. AU - Chirgadze,N Y, AU - Sall,D J, AU - Briggs,S L, AU - Clawson,D K, AU - Zhang,M, AU - Smith,G F, AU - Schevitz,R W, PY - 2000/3/30/pubmed PY - 2000/5/16/medline PY - 2000/3/30/entrez SP - 29 EP - 36 JF - Protein science : a publication of the Protein Society JO - Protein Sci VL - 9 IS - 1 N2 - The crystal structures of four active site-directed thrombin inhibitors, 1-4, in a complex with human alpha-thrombin have been determined and refined at up to 2.0 A resolution using X-ray crystallography. These compounds belong to a structurally novel family of inhibitors based on a 2,3-disubstituted benzo[b]thiophene structure. Compared to traditional active-site directed inhibitors, the X-ray crystal structures of these complexes reveal a novel binding mode. Unexpectedly, the lipophilic benzo[b]thiophene nucleus of the inhibitor appears to bind in the S1 specificity pocket. At the same time, the basic amine of the C-3 side chain of the inhibitor interacts with the mostly hydrophobic proximal, S2, and distal, S3, binding sites. The second, basic amine side chain at C-2 was found to point away from the active site, occupying a location between the S1 and S1' sites. Together, the aromatic rings of the C-2 and C-3 side chains sandwich the indole ring of Trp60D contained in the thrombin S2 insertion loop defined by the sequence "Tyr-Pro-Pro-Trp." [The thrombin residue numbering used in this study is equivalent to that reported for chymotrypsinogen (Hartley BS, Shotton DM, 1971, The enzymes, vol. 3. New York: Academic Press. pp 323-373).] In contrast to the binding mode of more classical thrombin inhibitors (D-Phe-Pro-Arg-H, NAPAP, Argatroban), this novel class of benzo[b]thiophene derivatives does not engage in hydrogen bond formation with Gly216 of the thrombin active site. A detailed analysis of the three-dimensional structures not only provides a clearer understanding of the interaction of these agents with thrombin, but forms a foundation for rational structure-based drug design. The use of the data from this study has led to the design of derivatives that are up to 2,900-fold more potent than the screening hit 1. SN - 0961-8368 UR - https://www.unboundmedicine.com/medline/citation/10739244/The_crystal_structures_of_human_alpha_thrombin_complexed_with_active_site_directed_diamino_benzo[b]thiophene_derivatives:_a_binding_mode_for_a_structurally_novel_class_of_inhibitors_ L2 - https://doi.org/10.1110/ps.9.1.29 DB - PRIME DP - Unbound Medicine ER -