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In-Silico studies on opioid receptors and ligands : Understanding the structural basis of protein-ligand interactions and designing ligands with improved therapeutic profile

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Title In-Silico studies on opioid receptors and ligands : Understanding the structural basis of protein-ligand interactions and designing ligands with improved therapeutic profile
 
Creator Bera, Indrani
 
Subject Structural Biology & Bioinformatics
 
Description The present thesis entitled “In-silico studies on opioid receptors and ligands: Understanding the structural basis of protein-ligand interactions and designing ligands with improved therapeutic profile”, is based on application of computational approaches for getting insights into the structural requirements of ligands for binding to opioid receptors and identification of agonists acting at opioid receptors. Designing new agonists for opioid receptors is an active area of research due to the side-effect profile associated with the present opioid drugs as analgesics. The thesis covers five chapters. Chapter 1 consists of two parts. The first part provides an overview of opioid receptors and ligands, which includes uses of opioids, side effects of using opioids as therapeutics and the need for new opioids with better therapeutic profile. The second part of this chapter gives a broad overview of molecular modeling methods and in-silico tools, used in computer aided drug designing. Chapter 1 ends with the objective and relevance of the present study. Chapter 2 deals with generating homology models of three opioid receptors (mu,kappa and delta) based on single and multiple templates. Multiple templates are supposed to increase the sequence similarity of the query sequence with the target sequences and consequently may result in better homology models. To investigate the advantage of using multiple templates, a comparative study was performed for assessing the structural quality of the homology models based on single and multiple templates. Structural qualities of the homology models were checked with standard tools used for validating homology models. The results obtained from this study shows that the use of multiple templates not always helps in generating structurally better 3D models. Chapter 3 deals with identifying the interactions leading to binding of kappa opioid agonists into the binding site of kappa opioid receptor. In this study, two nitrogen containing non-peptidic kappa opioid agonists, one non-protonated and the other protonated, were docked using induced fit docking. From this study, differences between interactions of protonated and non-protonated kappa opioid agonists have been visualised. In Chapter 4, the 2D-QSAR studies, performed on a series of aminomorphinan ligands having dual agonistic activities towards mu and kappa opioid receptors, have been described. The QSAR models were developed individually for activities towards both the receptors using a set of descriptors. GFA and G/PLS were used as regression techniques. A common feature pharmacophore was generated and used for aligning the compounds for CoMFA based 3D-QSAR studies. All the QSAR models were validated using important statistical metrices and checked for applicability domains. Bioactive conformation of the compound having high and comparable activity for both the receptors was used for ROCS based virtual screening of ZINC database. The obtained hits were enriched using various in silico methods and the activities of the hits were predicted using the QSAR models having best external predictability. As an outcome of this study, a novel in silico protocol was developed for identifying hits which may be considered as prospective dual agonists for mu and kappa opioid receptors.Chapter 5 summarizes the entire research component of the thesis.
 
Date 2014
 
Type Thesis
NonPeerReviewed
 
Format application/pdf
 
Identifier http://www.eprints.iicb.res.in/2090/1/Thesis_Indrani_Bera.pdf
Bera, Indrani (2014) In-Silico studies on opioid receptors and ligands : Understanding the structural basis of protein-ligand interactions and designing ligands with improved therapeutic profile. PhD thesis, Jadavpur University.
 
Relation http://www.eprints.iicb.res.in/2090/