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      Current progress in Structure-Based Rational Drug Design marks a new mindset in drug discovery

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          Abstract

          The past decade has witnessed a paradigm shift in preclinical drug discovery with structure-based drug design (SBDD) making a comeback while high-throughput screening (HTS) methods have continued to generate disappointing results. There is a deficit of information between identified hits and the many criteria that must be fulfilled in parallel to convert them into preclinical candidates that have a real chance to become a drug. This gap can be bridged by investigating the interactions between the ligands and their receptors. Accurate calculations of the free energy of binding are still elusive; however progresses were made with respect to how one may deal with the versatile role of water. A corpus of knowledge combining X-ray structures, bioinformatics and molecular modeling techniques now allows drug designers to routinely produce receptor homology models of increasing quality. These models serve as a basis to establish and validate efficient rationales used to tailor and/or screen virtual libraries with enhanced chances of obtaining hits. Many case reports of successful SBDD show how synergy can be gained from the combined use of several techniques. The role of SBDD with respect to two different classes of widely investigated pharmaceutical targets: (a) protein kinases (PK) and (b) G-protein coupled receptors (GPCR) is discussed. Throughout these examples prototypical situations covering the current possibilities and limitations of SBDD are presented.

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          Most cited references104

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          Crystal structure of the human beta2 adrenergic G-protein-coupled receptor.

          Structural analysis of G-protein-coupled receptors (GPCRs) for hormones and neurotransmitters has been hindered by their low natural abundance, inherent structural flexibility, and instability in detergent solutions. Here we report a structure of the human beta2 adrenoceptor (beta2AR), which was crystallized in a lipid environment when bound to an inverse agonist and in complex with a Fab that binds to the third intracellular loop. Diffraction data were obtained by high-brilliance microcrystallography and the structure determined at 3.4 A/3.7 A resolution. The cytoplasmic ends of the beta2AR transmembrane segments and the connecting loops are well resolved, whereas the extracellular regions of the beta2AR are not seen. The beta2AR structure differs from rhodopsin in having weaker interactions between the cytoplasmic ends of transmembrane (TM)3 and TM6, involving the conserved E/DRY sequences. These differences may be responsible for the relatively high basal activity and structural instability of the beta2AR, and contribute to the challenges in obtaining diffraction-quality crystals of non-rhodopsin GPCRs.
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            Crystal structure of opsin in its G-protein-interacting conformation.

            Opsin, the ligand-free form of the G-protein-coupled receptor rhodopsin, at low pH adopts a conformationally distinct, active G-protein-binding state known as Ops*. A synthetic peptide derived from the main binding site of the heterotrimeric G protein-the carboxy terminus of the alpha-subunit (GalphaCT)-stabilizes Ops*. Here we present the 3.2 A crystal structure of the bovine Ops*-GalphaCT peptide complex. GalphaCT binds to a site in opsin that is opened by an outward tilt of transmembrane helix (TM) 6, a pairing of TM5 and TM6, and a restructured TM7-helix 8 kink. Contacts along the inner surface of TM5 and TM6 induce an alpha-helical conformation in GalphaCT with a C-terminal reverse turn. Main-chain carbonyl groups in the reverse turn constitute the centre of a hydrogen-bonded network, which links the two receptor regions containing the conserved E(D)RY and NPxxY(x)(5,6)F motifs. On the basis of the Ops*-GalphaCT structure and known conformational changes in Galpha, we discuss signal transfer from the receptor to the G protein nucleotide-binding site.
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              Conformational complexity of G-protein-coupled receptors.

              G-protein-coupled receptors (GPCRs) are remarkably versatile signaling molecules. Members of this large family of membrane proteins respond to structurally diverse ligands and mediate most transmembrane signal transduction in response to hormones and neurotransmitters, and in response to the senses of sight, smell and taste. Individual GPCRs can signal through several G-protein subtypes and through G-protein-independent pathways, often in a ligand-specific manner. This functional plasticity can be attributed to structural flexibility of GPCRs and the ability of ligands to induce or to stabilize ligand-specific conformations. Here, we review what has been learned about the dynamic nature of the structure and mechanism of GPCR activation, primarily focusing on spectroscopic studies of purified human beta2 adrenergic receptor.
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                Author and article information

                Journal
                Comput Struct Biotechnol J
                Comput Struct Biotechnol J
                CSBJ
                Computational and Structural Biotechnology Journal
                Research Network of Computational and Structural Biotechnology (RNCSB) Organization
                2001-0370
                02 April 2013
                2013
                : 5
                : e201302011
                Affiliations
                [a ]CMBI, NCMLS Radboud University, Nijmegen Medical Centre, Geert Grooteplein 26-28, 6525 GA Nijmegen, The Netherlands
                [b ]Computational Drug Discovery, CMBI, NCMLS, Radboud University Medical Centre, Geert Grooteplein 26-28, 6525 GA Nijmegen, The Netherlands
                [c ]Beethovengaarde 97, 5344 CD Oss, The Netherlands
                [d ]BioAxis Research BV, Pivot Park, Molenstraat 110, 5342 CC Oss, The Netherlands
                [e ]Magdalen College, High Street, Oxford OX1 4AU, United Kingdom
                [f ]51 Natal Road, Cambridge, United KingdomUK
                Author notes
                Citation
                Lounnas V, Ritschel T, Kelder J, McGuire R, Bywater RP, Foloppe N (2013) Current progress in Structure-Based Rational Drug Design marks a new mindset in drug discovery. Computational and Structural Biotechnology Journal. 5 (6): e201302011. doi: http://dx.doi.org/10.5936/csbj.201302011
                [* ] Corresponding author: Tel.: +33 490221789. E-mail address: v-lounnas@ 123456unicancer.fr (Valère Lounnas)
                Article
                CSBJ-5-e201302011
                10.5936/csbj.201302011
                3962124
                24688704
                7cee78fc-3ad1-400c-9b9d-903c9cac7101
                © Lounnas et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly cited.

                History
                : 31 October 2012
                : 26 January 2013
                : 08 February 2013
                Categories
                Mini Reviews

                rational drug design,virtual screening,protein kinase,g-protein coupled receptors,ligand binding thermodynamics

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