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      Quantification of free ligand conformational preferences by NMR and their relationship to the bioactive conformation

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          Abstract

          Accurate unbound solution 3D-structures of ligands provide unique opportunities for medicinal chemistry and, in particular, a context to understand binding thermodynamics and kinetics. Previous methods of deriving these 3D-structures have had neither the accuracy nor resolution needed for drug design and have not yet realized their potential. Here, we describe and apply a NMR methodology to the aminoglycoside streptomycin that can accurately quantify accessible 3D-space and rank the occupancy of observed conformers to a resolution that enables medicinal chemistry understanding and design. Importantly, it is based upon conventional small molecule NMR techniques and can be performed in physiologically-relevant solvents. The methodology uses multiple datasets, an order of magnitude more experimental data than previous NMR approaches and a dynamic model during refinement, is independent of computational chemistry and avoids the problem of virtual conformations. The refined set of solution 3D-shapes for streptomycin can be grouped into two major families, of which the most populated is almost identical to the 30S ribosomal subunit bioactive shape. We therefore propose that accurate unbound ligand solution conformations may, in some cases, provide a subsidiary route to bioactive shape without crystallography. This experimental technique opens up new opportunities for drug design and more so when complemented with protein co-crystal structures, SAR data and pharmacophore modeling.

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          Most cited references50

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          Integrated Modeling Program, Applied Chemical Theory (IMPACT).

          We provide an overview of the IMPACT molecular mechanics program with an emphasis on recent developments and a description of its current functionality. With respect to core molecular mechanics technologies we include a status report for the fixed charge and polarizable force fields that can be used with the program and illustrate how the force fields, when used together with new atom typing and parameter assignment modules, have greatly expanded the coverage of organic compounds and medicinally relevant ligands. As we discuss in this review, explicit solvent simulations have been used to guide our design of implicit solvent models based on the generalized Born framework and a novel nonpolar estimator that have recently been incorporated into the program. With IMPACT it is possible to use several different advanced conformational sampling algorithms based on combining features of molecular dynamics and Monte Carlo simulations. The program includes two specialized molecular mechanics modules: Glide, a high-throughput docking program, and QSite, a mixed quantum mechanics/molecular mechanics module. These modules employ the IMPACT infrastructure as a starting point for the construction of the protein model and assignment of molecular mechanics parameters, but have then been developed to meet specialized objectives with respect to sampling and the energy function. (c) 2005 Wiley Periodicals, Inc.
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            Lessons from natural molecules.

            Natural products have inspired chemists and physicians for millennia. Their rich structural diversity and complexity has prompted synthetic chemists to produce them in the laboratory, often with therapeutic applications in mind, and many drugs used today are natural products or natural-product derivatives. Recent years have seen considerable advances in our understanding of natural-product biosynthesis. Coupled with improvements in approaches for natural-product isolation, characterization and synthesis, these could be opening the door to a new era in the investigation of natural products in academia and industry.
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              The Monte Carlo method.

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                Author and article information

                Contributors
                Journal
                Bioorg Med Chem
                Bioorg. Med. Chem
                Bioorganic & Medicinal Chemistry
                Elsevier Science
                0968-0896
                1464-3391
                01 September 2013
                01 September 2013
                : 21
                : 17
                : 4976-4987
                Affiliations
                C4X Discovery Ltd, Unit 310 Ducie House, Ducie Street, Manchester M1 2JW, UK
                AstraZeneca, Alderley Park, Cheshire SK10 4TG, UK
                Manchester Institute of Biotechnology and Faculty of Life Sciences, University of Manchester, 131 Princess Street, Manchester M1 7DN, UK
                Author notes
                Article
                BMC10949
                10.1016/j.bmc.2013.06.056
                3744816
                23886813
                bf8b16a5-f6c7-4a22-9f89-bfb9e72ff5c1
                © 2013 The Authors

                This document may be redistributed and reused, subject to certain conditions.

                History
                : 22 May 2013
                : 24 June 2013
                Categories
                Article

                Pharmaceutical chemistry
                nmr, nuclear magnetic resonance,csd, cambridge structural database,pdb, protein data bank,noe, nuclear overhauser enhancement,bioactive conformation,solution conformation,nmr,streptomycin,aminoglycoside,antibiotic,30s ribosomal subunit,ligand binding,pharmacophore,preorganization,virtual screening

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