title: How proteins bind macrocycles.
abstract: The potential utility of synthetic macrocycles (MCs) 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 MCs for good target protein-binding activity or bioavailability. To address this knowledge gap, we analyze the binding modes of a representative set of MC-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 MC libraries with structural and physicochemical features likely to favor strong binding to protein targets as well as good bioavailability. We additionally provide evidence that large, natural product-derived MCs can bind targets that are not druggable by conventional, drug-like compounds, supporting the notion that natural product-inspired synthetic MCs can expand the number of proteins that are druggable by synthetic small molecules.
authors.affiliation: Department of Chemistry, Boston University, Boston, Massachusetts, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Villar
authors.affiliation: Department of Biomedical Engineering, Boston University, Boston, Massachusetts, USA.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Beglov
authors.affiliation: Department of Chemistry, Boston University, Boston, Massachusetts, USA.
authors.forename: Spandan
authors.initials: S
authors.lastname: Chennamadhavuni
authors.affiliation: Department of Chemistry, Boston University, Boston, Massachusetts, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Porco
authors.affiliation: Department of Biomedical Engineering, Boston University, Boston, Massachusetts, USA.
authors.forename: Dima
authors.initials: D
authors.lastname: Kozakov
authors.affiliation: 1] Department of Chemistry, Boston University, Boston, Massachusetts, USA. [2] Department of Biomedical Engineering, Boston University, Boston, Massachusetts, USA.
authors.forename: Sandor
authors.initials: S
authors.lastname: Vajda
authors.affiliation: Department of Chemistry, Boston University, Boston, Massachusetts, USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Whitty
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D001682:Biological Availability; D018360:Crystallography, X-Ray; D015195:Drug Design; D047028:Macrocyclic Compounds / Q000378:metabolism*; D013058:Mass Spectrometry; D008958:Models, Molecular; D008970:Molecular Weight; D004364:Pharmaceutical Preparations / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects*; D011506:Proteins / Q000378:metabolism; D054852:Small Molecule Libraries
chemical_list: D047028:Macrocyclic Compounds; D004364:Pharmaceutical Preparations; D011506:Proteins; D054852:Small Molecule Libraries