Abstract
Uncontrolled kallikrein activation is involved in diseases such as hereditary angioedema, bacterial septic shock and procedures such as cardiopulmonary bypass. Here we report a series of small molecule compounds that potently inhibit kallikrein activity in vitro. Kinetic studies indicate that some of these compounds are slow binding inhibitors of kallikrein with Ki final less than a nanomolar. The ability of these compounds to inhibit the activity of kallikrein was further confirmed in a plasma model by quantitating the release of bradykinin, an endogenous cleavage product of plasma kallikrein. To understand the inhibitory mechanism of the selected compounds toward kallikrein, the interactions between the selected compounds and kallikrein was explored using molecular modeling based on the information of crystal structures of TF/FVIIa and kallikrein. The information presented in the current study provides an initial approach to develop more selective and therapeutically useful small molecule inhibitors.
Keywords: Kallikrein, contact activation, bradykinin, inhibitor, modeling
Medicinal Chemistry
Title: Discovery of Highly Potent Small Molecule Kallikrein Inhibitors
Volume: 2 Issue: 6
Author(s): J. Zhang, R. Krishnan, C. S. Arnold, E. Mattsson, J. M. Kilpatrick, S. Bantia, A. Dehghani, B. Boudreaux, S. N. Gupta, P.L. Kotian, P. Chand and Y.S. Babu
Affiliation:
Keywords: Kallikrein, contact activation, bradykinin, inhibitor, modeling
Abstract: Uncontrolled kallikrein activation is involved in diseases such as hereditary angioedema, bacterial septic shock and procedures such as cardiopulmonary bypass. Here we report a series of small molecule compounds that potently inhibit kallikrein activity in vitro. Kinetic studies indicate that some of these compounds are slow binding inhibitors of kallikrein with Ki final less than a nanomolar. The ability of these compounds to inhibit the activity of kallikrein was further confirmed in a plasma model by quantitating the release of bradykinin, an endogenous cleavage product of plasma kallikrein. To understand the inhibitory mechanism of the selected compounds toward kallikrein, the interactions between the selected compounds and kallikrein was explored using molecular modeling based on the information of crystal structures of TF/FVIIa and kallikrein. The information presented in the current study provides an initial approach to develop more selective and therapeutically useful small molecule inhibitors.
Export Options
About this article
Cite this article as:
Zhang J., Krishnan R., Arnold S. C., Mattsson E., Kilpatrick M. J., Bantia S., Dehghani A., Boudreaux B., Gupta N. S., Kotian P.L., Chand P. and Babu Y.S., Discovery of Highly Potent Small Molecule Kallikrein Inhibitors, Medicinal Chemistry 2006; 2 (6) . https://dx.doi.org/10.2174/1573406410602060545
DOI https://dx.doi.org/10.2174/1573406410602060545 |
Print ISSN 1573-4064 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6638 |
Call for Papers in Thematic Issues
Carbohydrates in Computational and Medicinal Chemistry
Carbohydrates are the most essential organic molecules and are involved in the maintenance of various physiological and metabolic processes in living organisms. Carbohydrate-based compounds have come to the attention of researchers because of their significant contributions to biological functions, such as cell development and cell proliferation, connections between several cells, ...read more
Recent Advances in the Medicinal Chemistry of Cancer
Scope of the Thematic Issue: Correlation between structure and function is one of the important aspects of the success of anti-cancer compounds associated with their structure-activity interactions, physiology, biochemical, molecular, and genetic processes. Overcoming these obstacles is key to obtaining further insights into developments in rational drug design, bioorganic chemistry, ...read more
- 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
-
Advances in Inhibitors of FXa
Current Drug Targets Novel Possible Pharmaceutical Research Tools: Stem Cells, Gene Delivery and their Combination
Current Pharmaceutical Design Medicinal Plants with Multiple Effects on Cardiovascular Diseases: A Systematic Review
Current Pharmaceutical Design Structure Based Drug Design of Angiotensin-I Converting Enzyme Inhibitors
Current Medicinal Chemistry Natural Rubber Latex Allergy in Pediatric Patients
Current Pediatric Reviews The Shift in the “Paradigm” of the Pharmacology of Hypertension
Current Topics in Medicinal Chemistry Immediate Hypersensitivity Reactions to Penicillins and Other Betalactams
Current Pharmaceutical Design Allergen-Induced Inflammation
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry Monoclonal Antibodies in Allergy; Updated Applications and Promising Trials
Recent Patents on Inflammation & Allergy Drug Discovery The Use of N-Acetylcysteine in Respiratory Diseases
Current Respiratory Medicine Reviews A Closer Look to Polyesters: Properties, Synthesis, Characterization, and Particle Drug Delivery Applications
Nanoscience & Nanotechnology-Asia Human Plasma Kallikrein-Kinin System: Physiological and Biochemical Parameters
Cardiovascular & Hematological Agents in Medicinal Chemistry Macrolides Allergy
Current Pharmaceutical Design Adenovirus Vectors and Subviral Particles for Protein and Peptide Delivery
Current Gene Therapy Drug-Induced Aseptic Meningitis
Current Drug Targets - Immune, Endocrine & Metabolic Disorders Genetic Predictors of Drug Hypersensitivity
Current Pharmaceutical Design Non-glycemic Adverse Effects of Insulin
Current Diabetes Reviews A Brief Review of the Essential Role of Nanovehicles for Improving the Therapeutic Efficacy of Pharmacological Agents Against Tumours
Current Drug Delivery Proniosomes in Transdermal Drug Delivery
Current Pharmaceutical Design Efficacy and Safety Profile of Aliskiren: Practical Implications for Clinicians
Current Drug Safety