Abstract
Peptide mimetic compounds 9d and 9h showed good selectivity for FVIIa/TF over other serine proteases. Xray crystal structure analysis revealed that a large moiety at P3 interacted in a novel manner with the 170-loop and was accompanied by ligand-induced conformational change of the 170-loop. From additional optimization, we discovered compound 10b, an excellent extrinsic pathway-selective inhibitor.
Keywords: Structure-based drug design, Serine protease, FVIIa inhibitor, 2 x APTT/2 x PT ratio, X-ray crystal structure, Ligand-induced conformational change
Letters in Drug Design & Discovery
Title: Structure-Based Drug Design of Peptide Mimetics Containing Large P3 Moieties as Inhibitors of Factor VIIa
Volume: 6 Issue: 2
Author(s): Kunihiro Hattori, Toshiro Kozono, Haruhiko Sato, Masateru Ohta, Keiko Esaki, Takehisa Kitazawa, Kazutaka Yoshihashi, Akihisa Sakamoto, Yoshiaki Watanabe, Takuya Shiraishi, Takaki Koga, Tohru Esaki, Hitoshi Iikura, Yoshiyuki Ono, Hirofumi Kodama, Masayuki Haramura and Shojiro Kadono
Affiliation:
Keywords: Structure-based drug design, Serine protease, FVIIa inhibitor, 2 x APTT/2 x PT ratio, X-ray crystal structure, Ligand-induced conformational change
Abstract: Peptide mimetic compounds 9d and 9h showed good selectivity for FVIIa/TF over other serine proteases. Xray crystal structure analysis revealed that a large moiety at P3 interacted in a novel manner with the 170-loop and was accompanied by ligand-induced conformational change of the 170-loop. From additional optimization, we discovered compound 10b, an excellent extrinsic pathway-selective inhibitor.
Export Options
About this article
Cite this article as:
Hattori Kunihiro, Kozono Toshiro, Sato Haruhiko, Ohta Masateru, Esaki Keiko, Kitazawa Takehisa, Yoshihashi Kazutaka, Sakamoto Akihisa, Watanabe Yoshiaki, Shiraishi Takuya, Koga Takaki, Esaki Tohru, Iikura Hitoshi, Ono Yoshiyuki, Kodama Hirofumi, Haramura Masayuki and Kadono Shojiro, Structure-Based Drug Design of Peptide Mimetics Containing Large P3 Moieties as Inhibitors of Factor VIIa, Letters in Drug Design & Discovery 2009; 6 (2) . https://dx.doi.org/10.2174/157018009787582606
DOI https://dx.doi.org/10.2174/157018009787582606 |
Print ISSN 1570-1808 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-628X |
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Rosiglitazone Does Not Improve Cognition or Global Function when Used as Adjunctive Therapy to AChE Inhibitors in Mild-to-Moderate Alzheimers Disease: Two Phase 3 Studies
Current Alzheimer Research Legumes: A Healthy and Ecological Source of Flavonoids
Current Nutrition & Food Science Cannabinoid Signaling in Glial Cells in Health and Disease
Current Neuropharmacology The Endocannabinoid System and Heart Disease: The Role of Cannabinoid Receptor Type 2
Cardiovascular & Hematological Disorders-Drug Targets Baroreflex Function: Determinants in Healthy Subjects and Disturbances in Diabetes, Obesity and Metabolic Syndrome
Current Diabetes Reviews Important Role of Relaxation Techniques in Immune Functions, Glycemic Control, and Stress in Diabetic Patients with COVID-19: A Review
Current Diabetes Reviews Pharmacological Treatment of Hypertension in Pregnancy
Current Pharmaceutical Design Second-Generation Tyrosine Kinase Inhibitors as First-Line Treatment Strategy in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia Patients
Current Cancer Drug Targets Associations of Two Common Polymorphisms in <i>MTHFR</i> Gene with Blood Lipids and Therapeutic Efficacy of Simvastatin
Current Pharmaceutical Design On Electromagnetic Ablation of Biological Tissues: A Review
Recent Patents on Electrical Engineering Italian Association of Clinical Endocrinologists (AME) and Italian AACE Chapter Position Statement for Clinical Practice: Acromegaly - Part 1: Diagnostic and Clinical Issues
Endocrine, Metabolic & Immune Disorders - Drug Targets Multiple Forms of Proteasomes and their Role in Tumor Fate
Recent Patents on Endocrine, Metabolic & Immune Drug Discovery Neuropeptide Y Induces Cardiomyocyte Hypertrophy <i>via</i> Attenuating miR-29a-3p in Neonatal Rat Cardiomyocytes
Protein & Peptide Letters Processing of Terrestrial Laser Scanning Point Cloud Data for Computational Modelling of Building Facades
Recent Patents on Computer Science Cardiovascular Diseases and the Nitric Oxide Pathway
Current Vascular Pharmacology Ion Channel Defects in Idiopathic Epilepsies
Current Pharmaceutical Design Rhabdomyolysis in an HIV-Infected Patient on Anti-Retroviral Therapy Precipitated by High-Dose Pravastatin
Current Drug Safety Colchicine in Post-operative Atrial Fibrillation: A Review
Current Pharmaceutical Design Preventing Atherosclerosis with Angiotensin-Converting Enzyme Inhibitors: Emphasis on Diabetic Atherosclerosis
Current Drug Targets - Cardiovascular & Hematological Disorders The Role of the Urokinase Receptor in Epilepsy, in Disorders of Language, Cognition, Communication and Behavior, and in the Central Nervous System
Current Pharmaceutical Design