Abstract
Direct renin inhibitors (DRIs) have increasingly shown a significant advantage in the treatment of hypertension and protection of target organs. In this paper, a series of azaindole class renin inhibitors were subjected to 3D-QSAR study using Topomer CoMFA. Five kinds of splitting mode for different fragment cutting and 6 different training and test sets grouping were attempted to build consensus models. The results indicated that 6 consensus models had similar predictability (q2 and r2 pred) and stability (r2). The best model showed good stability and predictability (q2 of 0.616, r2 of 0.908). The r2 pred value of the external test set was 0.70, which means that the model had an excellent external predictive ability, and the robustness of the developed model was assessed by the Y-randomization test. This study also adopted the methodology of fragment-based drug design (FBDD) to virtual screen new renin inhibitors by using Topomer Search technology. The R1-group of the compound No. 13 with the highest activity was chosen as the basic scaffold, and its remaining R2-group acted as a query to screen 142,025 molecules of ZINC database for similar fragments. The obtained 30 fragments with the highest R2-group contribution values were added to the basic scaffold respectively. Finally 30 new azaindole compounds with potent high activities were obtained. Further the binding modes were studied by using Surflex- Dock. The docking results showed good binding interactions of the designed compounds with the renin protein, thus the rationality of this design was further verified from the perspective of the renin receptor.
Keywords: Fragment-based drug design, renin inhibitors, surflex-dock, topomer CoMFA, topomer search, virtual screening.
Combinatorial Chemistry & High Throughput Screening
Title:Topomer CoMFA and Virtual Screening Studies of Azaindole Class Renin Inhibitors
Volume: 17 Issue: 5
Author(s): Yuhong Xiang, Jia Song and Zhuoyong Zhang
Affiliation:
Keywords: Fragment-based drug design, renin inhibitors, surflex-dock, topomer CoMFA, topomer search, virtual screening.
Abstract: Direct renin inhibitors (DRIs) have increasingly shown a significant advantage in the treatment of hypertension and protection of target organs. In this paper, a series of azaindole class renin inhibitors were subjected to 3D-QSAR study using Topomer CoMFA. Five kinds of splitting mode for different fragment cutting and 6 different training and test sets grouping were attempted to build consensus models. The results indicated that 6 consensus models had similar predictability (q2 and r2 pred) and stability (r2). The best model showed good stability and predictability (q2 of 0.616, r2 of 0.908). The r2 pred value of the external test set was 0.70, which means that the model had an excellent external predictive ability, and the robustness of the developed model was assessed by the Y-randomization test. This study also adopted the methodology of fragment-based drug design (FBDD) to virtual screen new renin inhibitors by using Topomer Search technology. The R1-group of the compound No. 13 with the highest activity was chosen as the basic scaffold, and its remaining R2-group acted as a query to screen 142,025 molecules of ZINC database for similar fragments. The obtained 30 fragments with the highest R2-group contribution values were added to the basic scaffold respectively. Finally 30 new azaindole compounds with potent high activities were obtained. Further the binding modes were studied by using Surflex- Dock. The docking results showed good binding interactions of the designed compounds with the renin protein, thus the rationality of this design was further verified from the perspective of the renin receptor.
Export Options
About this article
Cite this article as:
Xiang Yuhong, Song Jia and Zhang Zhuoyong, Topomer CoMFA and Virtual Screening Studies of Azaindole Class Renin Inhibitors, Combinatorial Chemistry & High Throughput Screening 2014; 17 (5) . https://dx.doi.org/10.2174/1386207317666140107094708
DOI https://dx.doi.org/10.2174/1386207317666140107094708 |
Print ISSN 1386-2073 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5402 |
Call for Papers in Thematic Issues
Artificial Intelligence Methods for Biomedical, Biochemical and Bioinformatics Problems
Recently, a large number of technologies based on artificial intelligence have been developed and applied to solve a diverse range of problems in the areas of biomedical, biochemical and bioinformatics problems. By utilizing powerful computing resources and massive amounts of data, methods based on artificial intelligence can significantly improve the ...read more
Eco-friendly Agents for Biological Control of Pathogenic Diseases
The discovery of an alternative biological approach to disease management includes work on medicinal products derived from natural sources as a starting point for the development of eco-friendly agents for these diseases and the injuries they cause, as well as reducing human contact with hazardous chemicals and their residues. We ...read more
Emerging trends in diseases mechanisms, noble drug targets and therapeutic strategies: focus on immunological and inflammatory disorders
Recently infectious and inflammatory diseases have been a key concern worldwide due to tremendous morbidity and mortality world Wide. Recent, nCOVID-9 pandemic is a good example for the emerging infectious disease outbreak. The world is facing many emerging and re-emerging diseases out breaks at present however, there is huge lack ...read more
Exploring Spectral Graph Theory in Combinatorial Chemistry
Scope of the Thematic Issue: Combinatorial chemistry involves the synthesis and analysis of a large number of diverse compounds simultaneously. Traditional methods rely on brute force experimentation, which can be time-consuming and resource-intensive. Spectral Graph Theory, a branch of mathematics dealing with the properties of graphs in relation to the ...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
-
Aliskiren: A New Drug for an Old Problem
Cardiovascular & Hematological Agents in Medicinal Chemistry Nummular Eczema: An Updated Review
Recent Patents on Inflammation & Allergy Drug Discovery The Safety of Allergen Specific Sublingual Immunotherapy
Current Drug Safety Cow’s Milk Allergy: Where have we Come from and where are we Going?
Endocrine, Metabolic & Immune Disorders - Drug Targets What Does a Pediatrician Need to Know About Chronic Diarrhea?
Current Pediatric Reviews A Systematic Approach to Assess the Burden of Drug Interactions in Adult Kidney Transplant Patients
Current Drug Safety Target Product Selection - Where Can Molecular Pharming Make the Difference?
Current Pharmaceutical Design Challenges in the Management of Severe Asthma: Role of Current and Future Therapies
Current Pharmaceutical Design Seasonal Allergic Rhinitis
Recent Patents on Inflammation & Allergy Drug Discovery Anti-GD2 Antibody Therapy for GD2-Expressing Tumors
Current Cancer Drug Targets Antiepileptic Drug-Induced Hypersensitivity Syndrome Reactions
Current Drug Safety Cytokine and Nitric Oxide Production Following Severe Envenomation
Current Drug Targets - Inflammation & Allergy The Shift in the “Paradigm” of the Pharmacology of Hypertension
Current Topics in Medicinal Chemistry Successful Desensitization of Three Patients with Hypersensitivity Reactions to Omalizumab
Current Drug Safety Renin Angiotensin System (RAS) and Immune System Profile in Specific Subgroups with COVID-19
Current Medicinal Chemistry A Brief Review of the Essential Role of Nanovehicles for Improving the Therapeutic Efficacy of Pharmacological Agents Against Tumours
Current Drug Delivery New Antihypertensive Drugs Under Development
Current Medicinal Chemistry Efficacy and Safety Profile of Aliskiren: Practical Implications for Clinicians
Current Drug Safety A Case of Pantoprazole Anaphylaxis with Cross Reactivity to All Proton Pump Inhibitors: Finding a Safe Alternative
Current Drug Safety Methylene Blue and Vasoplegia: Who, When, and How?
Mini-Reviews in Medicinal Chemistry