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      How Proteins Bind Macrocycles

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          Abstract

          The potential utility of synthetic macrocycles as drugs, particularly against low druggability targets such as protein-protein interactions, has been widely discussed. There is little information, however, to guide the design of macrocycles for good target protein-binding activity or bioavailability. To address this knowledge gap we analyze the binding modes of a representative set of macrocycle-protein complexes. The results, combined with consideration of the physicochemical properties of approved macrocyclic drugs, allow us to propose specific guidelines for the design of synthetic macrocycles libraries possessing structural and physicochemical features likely to favor strong binding to protein targets and also good bioavailability. We additionally provide evidence that large, natural product derived macrocycles can bind to targets that are not druggable by conventional, drug-like compounds, supporting the notion that natural product inspired synthetic macrocycles can expand the number of proteins that are druggable by synthetic small molecules.

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          Most cited references 41

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          The interpretation of protein structures: estimation of static accessibility.

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            Ligand efficiency: a useful metric for lead selection.

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              The atomic structure of protein-protein recognition sites.

              The non-covalent assembly of proteins that fold separately is central to many biological processes, and differs from the permanent macromolecular assembly of protein subunits in oligomeric proteins. We performed an analysis of the atomic structure of the recognition sites seen in 75 protein-protein complexes of known three-dimensional structure: 24 protease-inhibitor, 19 antibody-antigen and 32 other complexes, including nine enzyme-inhibitor and 11 that are involved in signal transduction.The size of the recognition site is related to the conformational changes that occur upon association. Of the 75 complexes, 52 have "standard-size" interfaces in which the total area buried by the components in the recognition site is 1600 (+/-400) A2. In these complexes, association involves only small changes of conformation. Twenty complexes have "large" interfaces burying 2000 to 4660 A2, and large conformational changes are seen to occur in those cases where we can compare the structure of complexed and free components. The average interface has approximately the same non-polar character as the protein surface as a whole, and carries somewhat fewer charged groups. However, some interfaces are significantly more polar and others more non-polar than the average. Of the atoms that lose accessibility upon association, half make contacts across the interface and one-third become fully inaccessible to the solvent. In the latter case, the Voronoi volume was calculated and compared with that of atoms buried inside proteins. The ratio of the two volumes was 1.01 (+/-0.03) in all but 11 complexes, which shows that atoms buried at protein-protein interfaces are close-packed like the protein interior. This conclusion could be extended to the majority of interface atoms by including solvent positions determined in high-resolution X-ray structures in the calculation of Voronoi volumes. Thus, water molecules contribute to the close-packing of atoms that insure complementarity between the two protein surfaces, as well as providing polar interactions between the two proteins. Copyright 1999 Academic Press.
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                Author and article information

                Journal
                101231976
                32624
                Nat Chem Biol
                Nat. Chem. Biol.
                Nature chemical biology
                1552-4450
                1552-4469
                17 June 2014
                20 July 2014
                September 2014
                03 May 2015
                : 10
                : 9
                : 723-731
                Affiliations
                [1 ]Departments of Chemistry University, Boston, Massachusetts 02215
                [2 ]Departments of Biomedical Engineering, Boston University, Boston, Massachusetts 02215
                Author notes
                To whom correspondence should be addressed: whitty@ 123456bu.edu ; vajda@ 123456bu.edu ; midas@ 123456bu.edu
                Article
                NIHMS605065
                10.1038/nchembio.1584
                4417626
                25038790

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                Categories
                Article

                Biochemistry

                druglikeness, druggability, ligand efficiency, binding mode, macrocyclic drugs

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