1,721,191 research outputs found
An overview of recent developments in GPCR modelling: methods and validation
No full textThe superfamily of G-protein-coupled receptors (GPCRs) are single polypeptide chains possessing seven hydrophobic transmembrane-spanning segments that couple with an effector molecule through a trimeric G protein complex. A knowledge of their three-dimensional structure could be of great help in the task of understanding their function and in the rational design of specific ligands. However, as GPCRs are membrane-bound proteins, high-resolution structural characterisation is still an extremely difficult task. For this reason, great importance has been placed on molecular modelling studies, and in the last few years especially on homology modelling (HM) techniques. The HM procedure starts from the recently resolved crystal structure of the bovine rhodopsin, but other experimental data such as site-directed mutagenesis and substituted-cysteine accessibility method studies are extremely necessary. In this review the most common HM computational steps are reported and discussed together with the most recent alternative approaches and main validation methods. Future possible targets of the HM are presented and expected improvements in computational methods are considered
Computational Approaches on Angiotensin Receptors and their Ligands: Recent Developments and Results
No full textAngiotensin II (AngII) is the major regulator of blood pressure, electrolyte balance, and some endocrine functions related to cardiovascular diseases. Moreover, it has been shown that AngII plays a role in various pathological situations involving tissue remodelling and in cancer. Two distinct subtypes of AngII receptors [type 1 (AT1) and type 2 (AT2)] have been identified, and both belong to the G protein-coupled receptor (GPCR) superfamily. A knowledge of the 3D structure of AT receptors could be of great help in the task of understanding molecular interactions, and in the rational design of specific ligands; however, as GPCRs are membrane-bound proteins, high-resolution structural characterization is still an extremely difficult task. For this reason, great importance has been placed on molecular modelling studies and in particular, on homology modelling (HM) techniques. In this review, we report and analyze the main experimental data and the computational procedures and validation methods used for the construction of the AT receptors, describing in details the most successful results and new trends
Computational Studies on Transthyretin
No full textAmong the 23 different fibril proteins described in human amyloidosis, transthyretin is associated with the most common hereditary form of the disease and its knowledge is corroborated through about 150 crystal structures in addition to thousands of small ligands tested as fibril formation inhibitors. In spite of the large amount of available data, the mechanism of transthyretin aggregation and its inhibition through binding with small ligands is not clear. In the last decade, many groups of researchers have attempted to apply computational procedures to simulate these phenomena, with the aim of understanding them in depth and in order to rationalize the design of new promising inhibitors. A summary of the main molecular dynamics, docking, and structure-activity relationship studies carried out on transthyretin are reviewed here, and the most successful results and new trends are described in detail
Computational Approaches for the Identification and Optimization of Src Family Kinases Inhibitors.
No full textSrc family kinases (SFKs) are a group of non-receptor tyrosine kinases whose activity is involved in the regulation of cellular morphology, motility, proliferation and survival. An aberrant activation and expression of these kinases contributes to the pathogenesis and progression of a broad range of diseases, such as a large number of solid tumors, various hematological malignancies and some neuronal pathologies. The search for SFK inhibitors is therefore a promising research topic in medicinal chemistry. Computational studies such as receptor-based and/or ligand-based virtual screening, docking, and molecular modeling proved to be a powerful tool for identifying new SFKs inhibitors. In this review we report and analyze the main examples of computational approaches that allowed the identification of new SFKs ligands and the optimization of either activity and pharmacokinetic profile of lead compounds
MO STUDIES ON THE MECHANISM OF DRUG-RECEPTOR INTERACTION .3. ADRENERGIC DRUG REACTIVITY OF TAZOLOL
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