Abstract
Salbutamol forms an important and widely administered β2 agonist prescribed in the symptomatic treatment of bronchial asthma. Unfortunately, a subset of patients show refractoriness to it owing to ADRB2 gene variant (rs 1800888). The variant substitutes Thr to Ile at the position 164 in the β2 adrenergic receptor leading to sub-optimal binding of agonists. The present study aims to associate the Salbutamol response with the variant and select the bioactive conformer of Sabutamol with optimal binding affinity against mutated receptor by in silico approaches. To assess bronchodilator response spirometry was performed before and 15 min after Salbutamol (200 mcg) inhalation. Responders to Salbutamol were categorized if percentage reversibility was greater than or equal to 12%, while those showing FEV1 reversibility less than 12% were classified as non-responders. Among the 344 subjects screened, 238 were responders and 106 were non-responders. The frequency of mutant allele “T” was significantly higher in case of non-responders (p < 0.05). In silico process involved generation of Salbutamol conformer ensembles supported by systematic search algorithm. 4369 conformers were generated of which only 1882 were considered bioactive conformers (threshold RMSD≤1 in reference to normalized structure of salbutamol). All the bioactive conformers were evaluated for the binding affinity against (Thr164 Ile) receptor through MolDock aided docking algorithm. One of the bioactive conformer (P.E. = -57.0038, RMSD = 0.6) demonstrated 1.54 folds greater affinity than the normal Salbutamol in the mutated receptor. The conformer identified in the present study may be put to pharmacodynamic and pharmacokinetic studies in future ahead.
Keywords: ADRB2 (rs 1800888) polymorphism, β2AR (Thr 164Ile), Salbutamol Bioactive Conformer, Salbutamol refractoriness.
Current Topics in Medicinal Chemistry
Title:Identification of High Affinity Bioactive Salbutamol Conformer Directed Against Mutated (Thr164Ile) Beta 2 Adrenergic Receptor
Volume: 15 Issue: 1
Author(s): Srinivas Bandaru, Geet Tiwari, Jyothy Akka, Vijaya Kumar Marri, Mallika Alvala, Venkata Ravi Gutlapalli, Anuraj Nayarisseri and Hema Prasad Mundluru
Affiliation:
Keywords: ADRB2 (rs 1800888) polymorphism, β2AR (Thr 164Ile), Salbutamol Bioactive Conformer, Salbutamol refractoriness.
Abstract: Salbutamol forms an important and widely administered β2 agonist prescribed in the symptomatic treatment of bronchial asthma. Unfortunately, a subset of patients show refractoriness to it owing to ADRB2 gene variant (rs 1800888). The variant substitutes Thr to Ile at the position 164 in the β2 adrenergic receptor leading to sub-optimal binding of agonists. The present study aims to associate the Salbutamol response with the variant and select the bioactive conformer of Sabutamol with optimal binding affinity against mutated receptor by in silico approaches. To assess bronchodilator response spirometry was performed before and 15 min after Salbutamol (200 mcg) inhalation. Responders to Salbutamol were categorized if percentage reversibility was greater than or equal to 12%, while those showing FEV1 reversibility less than 12% were classified as non-responders. Among the 344 subjects screened, 238 were responders and 106 were non-responders. The frequency of mutant allele “T” was significantly higher in case of non-responders (p < 0.05). In silico process involved generation of Salbutamol conformer ensembles supported by systematic search algorithm. 4369 conformers were generated of which only 1882 were considered bioactive conformers (threshold RMSD≤1 in reference to normalized structure of salbutamol). All the bioactive conformers were evaluated for the binding affinity against (Thr164 Ile) receptor through MolDock aided docking algorithm. One of the bioactive conformer (P.E. = -57.0038, RMSD = 0.6) demonstrated 1.54 folds greater affinity than the normal Salbutamol in the mutated receptor. The conformer identified in the present study may be put to pharmacodynamic and pharmacokinetic studies in future ahead.
Export Options
About this article
Cite this article as:
Bandaru Srinivas, Tiwari Geet, Akka Jyothy, Marri Kumar Vijaya, Alvala Mallika, Gutlapalli Ravi Venkata, Nayarisseri Anuraj and Mundluru Prasad Hema, Identification of High Affinity Bioactive Salbutamol Conformer Directed Against Mutated (Thr164Ile) Beta 2 Adrenergic Receptor, Current Topics in Medicinal Chemistry 2015; 15 (1) . https://dx.doi.org/10.2174/1568026615666150112113040
DOI https://dx.doi.org/10.2174/1568026615666150112113040 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...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
- Announcements
Related Articles
-
Up-Regulation of MBD1 Promotes Pancreatic Cancer Cell Epithelial-Mesenchymal Transition and Invasion by Epigenetic Down-Regulation of E-Cadherin
Current Molecular Medicine Synthesis and Antioxidant Activities of Ferrocenyl-containing Curcumin Analogues
Letters in Drug Design & Discovery 5-Fluorouracil Derivatives Induce Differentiation Mediated by Tubulin and HLA Class I Modulation
Medicinal Chemistry Cationicity and Hydrophobicity Enhance the Cytotoxic Potency of Phoratoxin C Anticancer Peptide Analogues against Triple Negative Breast Cancer Cells
Current Bioactive Compounds Malignant Mesothelioma: Biology, Diagnosis and Therapeutic Approaches
Current Molecular Pharmacology Intracellular Calcium Homeostasis and Kidney Disease
Current Medicinal Chemistry Targeted Delivery of Colloidal Silver for MCF-7 Breast Cancer Treatment
Current Drug Delivery Recent Development in Targeting PI3K-Akt-mTOR Signaling for Anticancer Therapeutic Strategies
Anti-Cancer Agents in Medicinal Chemistry Natural Products of Dietary Origin as Lead Compounds in Virtual Screening and Drug Design
Current Pharmaceutical Biotechnology Targeting JAK/STAT Signaling Pathway in Inflammatory Diseases
Current Signal Transduction Therapy Targeting Carcinogen Metabolism by Dietary Cancer Preventive Compounds
Current Cancer Drug Targets Biotransformation of Endocrine Disrupting Compounds by Selected Phase I and Phase II Enzymes – Formation of Estrogenic and Chemically Reactive Metabolites by Cytochromes P450 and Sulfotransferases
Current Medicinal Chemistry Pharmacoproteomics Applications for Drug Target Discovery in CNS Disorders
Current Pharmacogenomics and Personalized Medicine Liposomal Doxorubicin Delivery Systems: Effects of Formulation and Processing Parameters on Drug Loading and Release Behavior
Current Drug Delivery Cancer Drug Discovery Targeting Histone Methyltransferases: An Update
Current Medicinal Chemistry The Potential of 11C-acetate PET for Monitoring the Fatty Acid Synthesis Pathway in Tumors
Current Pharmaceutical Biotechnology Activation of Intrinsic Apoptosis and G1 Cell Cycle Arrest by a Triazole Precursor, N-(4-chlorophenyl)-2-(4-(3,4,5-trimethoxybenzyloxy)benzoyl)-hydrazinecarbothioamide in Breast Cancer Cell Line
Anti-Cancer Agents in Medicinal Chemistry Relevance of Protein Isoforms in Proteomic Studies
Current Proteomics Cancer Neovascularization and Proinflammatory Microenvironments
Current Cancer Drug Targets Commentary Research Highlights: Adaptive PTEN Loss Enhances the Outgrowth of Brain Metastatic Tumour Cells
CNS & Neurological Disorders - Drug Targets