How proteins bind macrocycles
| Autor: | Sandor Vajda, Dmitri Beglov, Dima Kozakov, Elizabeth A. Villar, John A. Porco, Spandan Chennamadhavuni, Adrian Whitty |
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| Rok vydání: | 2014 |
| Předmět: |
Models
Molecular Macrocyclic Compounds Druggability Biological Availability Drug design binding mode Plasma protein binding Crystallography X-Ray 010402 general chemistry 01 natural sciences Article Mass Spectrometry Small Molecule Libraries Binding site Molecular Biology Strong binding Binding Sites ligand efficiency 010405 organic chemistry Chemistry Drug discovery Proteins Cell Biology Small molecule Combinatorial chemistry 3. Good health 0104 chemical sciences Molecular Weight macrocyclic drugs Pharmaceutical Preparations Drug Design druglikeness druggability Protein Binding |
| Zdroj: | Nature chemical biology |
| ISSN: | 1552-4469 1552-4450 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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