Abstract
Modulation of gamma-secretase cleavage of Amyloid Precursor Protein (APP) to control the level of Amyloidbeta (A-beta) peptide is one of the strategies to develop therapy for Alzheimer’s disease. Presenilin is a subunit and the catalytic core of gamma-secretase. It has Asp 257 and Asp 385 residues, which are essential for catalytic activity and thus serve as the region of interest for screening of potential gamma-secretase inhibitors. In the present study, in silico screening of drug molecules has been performed in an attempt to identify effective inhibitors of presenilin. Ligand-based pharmacophore models generated with reported inhibitor molecules have been used as query for screening from DrugBank database. Inhibitory activity (IC50) of the screening hits is predicted using a QSAR model developed. The selected molecules have been subjected to docking study against Presenilin1 C-terminal fragment that houses Asp 385 in place of presenilin, as its structure is unavailable. Finally, 46 potential inhibitor molecules were selected based on scores of scoring function and interaction with Asp 385. The selected compounds have spatial arrangement of features essential for binding to presenilin, desired inhibitory activity against processing of APP to A-beta by gamma-secretase and selective interaction with specific amino acids in ligand-protein docked complexes.
Keywords: Alzheimer’s disease, drugs, gamma-secretase, IC50, inhibitors, ligand-based pharmacophore model, QSAR, screening.
Combinatorial Chemistry & High Throughput Screening
Title:In Silico Screening of Drugs to Find Potential Gamma-Secretase Inhibitors Using Pharmacophore Modeling, QSAR and Molecular Docking Studies
Volume: 17 Issue: 9
Author(s): Arun Ekiri Vaidyanathan Raman, Karthic Krishnan, Arun Maurya and Nandini Sarkar
Affiliation:
Keywords: Alzheimer’s disease, drugs, gamma-secretase, IC50, inhibitors, ligand-based pharmacophore model, QSAR, screening.
Abstract: Modulation of gamma-secretase cleavage of Amyloid Precursor Protein (APP) to control the level of Amyloidbeta (A-beta) peptide is one of the strategies to develop therapy for Alzheimer’s disease. Presenilin is a subunit and the catalytic core of gamma-secretase. It has Asp 257 and Asp 385 residues, which are essential for catalytic activity and thus serve as the region of interest for screening of potential gamma-secretase inhibitors. In the present study, in silico screening of drug molecules has been performed in an attempt to identify effective inhibitors of presenilin. Ligand-based pharmacophore models generated with reported inhibitor molecules have been used as query for screening from DrugBank database. Inhibitory activity (IC50) of the screening hits is predicted using a QSAR model developed. The selected molecules have been subjected to docking study against Presenilin1 C-terminal fragment that houses Asp 385 in place of presenilin, as its structure is unavailable. Finally, 46 potential inhibitor molecules were selected based on scores of scoring function and interaction with Asp 385. The selected compounds have spatial arrangement of features essential for binding to presenilin, desired inhibitory activity against processing of APP to A-beta by gamma-secretase and selective interaction with specific amino acids in ligand-protein docked complexes.
Export Options
About this article
Cite this article as:
Raman Ekiri Vaidyanathan Arun, Krishnan Karthic, Maurya Arun and Sarkar Nandini, In Silico Screening of Drugs to Find Potential Gamma-Secretase Inhibitors Using Pharmacophore Modeling, QSAR and Molecular Docking Studies, Combinatorial Chemistry & High Throughput Screening 2014; 17 (9) . https://dx.doi.org/10.2174/1386207317666141019195448
DOI https://dx.doi.org/10.2174/1386207317666141019195448 |
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
-
Structural Exploration of Synthetic Chromones as Selective MAO-B Inhibitors: A Mini Review
Combinatorial Chemistry & High Throughput Screening Editorial (Hot Topic: Achieving Current Goals in Prevention and Treatment of Vascular Disease: An Update)
Current Pharmaceutical Design Executive Dyscontrol in Dementia, with Emphasis on Subcortical Pathology and the Role of Butyrylcholinesterase
Current Alzheimer Research Amyloid β Accumulation Assessed with <sup>11</sup>C-Pittsburgh Compound B PET and Postmortem Neuropathology
Current Alzheimer Research Nanowired Drug Delivery to Enhance Neuroprotection in Spinal Cord Injury
CNS & Neurological Disorders - Drug Targets Psychometric Comparison of Standard and Computerized Administration of the Alzheimers Disease Assessment Scale – Cognitive Subscale (ADASCog)
Current Alzheimer Research Purinergic Signalling and Endothelium
Current Vascular Pharmacology Obstructive Sleep Apnea Syndrome: An Emerging Risk Factor for Dementia
CNS & Neurological Disorders - Drug Targets Circulating Aminopeptidase Activities in Men and Women with Essential Hypertension
Current Medicinal Chemistry C-Reactive Protein: Interaction with the Vascular Endothelium and Possible Role in Human Atherosclerosis
Current Pharmaceutical Design Geriatric Evaluation of Oncological Elderly Patients
Anti-Cancer Agents in Medicinal Chemistry Oxidative Stress and Amyloid Beta Toxicity in Alzheimer’s Disease: Intervention in a Complex Relationship by Antioxidants
Current Medicinal Chemistry Insights into the Role of Matrix Metalloproteinases and Tissue Inhibitor of Metalloproteinases in Health and Disease
Current Chemical Biology The Effects of Gender and CYP46 and Apo E Polymorphism on 24S-Hydroxycholesterol Levels in Alzheimers Patients Treated with Statins
Current Alzheimer Research Cognitive Reserve in Aging
Current Alzheimer Research Natural Triterpenoids and their Derivatives with Pharmacological Activity Against Neurodegenerative Disorders
Mini-Reviews in Organic Chemistry Lipoprotein (a) and Cardiovascular Risk: The Show Must go on
Current Medicinal Chemistry Physical and Mental Functions of Cardiovascular Diseased Patients Decrease During the State of Emergency Initiated by the COVID-19 Pandemic in Japan
Reviews on Recent Clinical Trials Treating the Cognitive Deficits of Schizophrenia with Alpha4Beta2 Neuronal Nicotinic Receptor Agonists
Current Pharmaceutical Design Protein Conformational Pathology in Alzheimers and Other Neurodegenerative Diseases; New Targets for Therapy
Current Alzheimer Research