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How proteins bind macrocycles.

Villar EA, Beglov D, Chennamadhavuni S, Porco JA, Kozakov D, Vajda S, Whitty A - Nat. Chem. Biol. (2014)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Boston University, Boston, Massachusetts, USA.

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.

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Extent and character of the protein-MC binding interface. (a) Plotof buried SASA versus total SASA. The dotted line represents the line of identity,corresponding to 100% of MC SASA buried in the complex. Small MCs (triangles) bury~80% of their SASA upon binding, with the size of the binding interfacebeing roughly proportional to the surface area of the MC ligand. The large MCs (circles)bury a roughly constant 630 ± 150 Å2 of SASA (dashed line),with only a small dependence on compound size. The solid curve is an arbitraryinterpolation of the data. (b) Comparison of the fraction of MC atoms thatmake direct contact with the protein (defined as atoms burying >5Å2 of MC SASA) that are polar versus nonpolar, versus thecorresponding ratio for all MC atoms. (c) Example showing how MC heavy atomscan be categorized by region into ring atoms (black), substituent atoms (blue) and“peripheral” atoms (green). (d) Contributions to total MCburied surface by region. (e) Percentage of atoms from each region that makedirect contact with the protein (defined as atoms burying >5 Å2of MC SASA). (f) Average polar/nonpolar ratio for the atoms from each MCregion that make contact with the protein. Error bars are standard deviations; an asterisk(*) indicates that the specified difference is statistically significant using theMann-Whitney U (rank) test (see Methods).
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Figure 3: Extent and character of the protein-MC binding interface. (a) Plotof buried SASA versus total SASA. The dotted line represents the line of identity,corresponding to 100% of MC SASA buried in the complex. Small MCs (triangles) bury~80% of their SASA upon binding, with the size of the binding interfacebeing roughly proportional to the surface area of the MC ligand. The large MCs (circles)bury a roughly constant 630 ± 150 Å2 of SASA (dashed line),with only a small dependence on compound size. The solid curve is an arbitraryinterpolation of the data. (b) Comparison of the fraction of MC atoms thatmake direct contact with the protein (defined as atoms burying >5Å2 of MC SASA) that are polar versus nonpolar, versus thecorresponding ratio for all MC atoms. (c) Example showing how MC heavy atomscan be categorized by region into ring atoms (black), substituent atoms (blue) and“peripheral” atoms (green). (d) Contributions to total MCburied surface by region. (e) Percentage of atoms from each region that makedirect contact with the protein (defined as atoms burying >5 Å2of MC SASA). (f) Average polar/nonpolar ratio for the atoms from each MCregion that make contact with the protein. Error bars are standard deviations; an asterisk(*) indicates that the specified difference is statistically significant using theMann-Whitney U (rank) test (see Methods).

Mentions: The small MCs tended to be almost fully enveloped within their protein bindingsites, burying a quite uniform 82 ± 4 % of their total solvent accessiblesurface area (SASA) upon binding (Figure 3a; Supplementary Table 3), asexemplified by Macbecin in its complex with hsp90 (Figure2c). In contrast, the large MCs appeared to bury a fairly uniform 630 ±120 Å2 of surface upon binding,corresponding to an average of 57 ± 8 % of the compounds’ totalSASA, with at most a modest dependence on MC size. This value is roughly twice the 300± 130 Å2 of SASA buried by a typicaldrug30, and approaches the 800± 200 Å2 of SASA buried on averageby each binding partner at a protein-protein interface31.


How proteins bind macrocycles.

Villar EA, Beglov D, Chennamadhavuni S, Porco JA, Kozakov D, Vajda S, Whitty A - Nat. Chem. Biol. (2014)

Extent and character of the protein-MC binding interface. (a) Plotof buried SASA versus total SASA. The dotted line represents the line of identity,corresponding to 100% of MC SASA buried in the complex. Small MCs (triangles) bury~80% of their SASA upon binding, with the size of the binding interfacebeing roughly proportional to the surface area of the MC ligand. The large MCs (circles)bury a roughly constant 630 ± 150 Å2 of SASA (dashed line),with only a small dependence on compound size. The solid curve is an arbitraryinterpolation of the data. (b) Comparison of the fraction of MC atoms thatmake direct contact with the protein (defined as atoms burying >5Å2 of MC SASA) that are polar versus nonpolar, versus thecorresponding ratio for all MC atoms. (c) Example showing how MC heavy atomscan be categorized by region into ring atoms (black), substituent atoms (blue) and“peripheral” atoms (green). (d) Contributions to total MCburied surface by region. (e) Percentage of atoms from each region that makedirect contact with the protein (defined as atoms burying >5 Å2of MC SASA). (f) Average polar/nonpolar ratio for the atoms from each MCregion that make contact with the protein. Error bars are standard deviations; an asterisk(*) indicates that the specified difference is statistically significant using theMann-Whitney U (rank) test (see Methods).
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Related In: Results  -  Collection

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Figure 3: Extent and character of the protein-MC binding interface. (a) Plotof buried SASA versus total SASA. The dotted line represents the line of identity,corresponding to 100% of MC SASA buried in the complex. Small MCs (triangles) bury~80% of their SASA upon binding, with the size of the binding interfacebeing roughly proportional to the surface area of the MC ligand. The large MCs (circles)bury a roughly constant 630 ± 150 Å2 of SASA (dashed line),with only a small dependence on compound size. The solid curve is an arbitraryinterpolation of the data. (b) Comparison of the fraction of MC atoms thatmake direct contact with the protein (defined as atoms burying >5Å2 of MC SASA) that are polar versus nonpolar, versus thecorresponding ratio for all MC atoms. (c) Example showing how MC heavy atomscan be categorized by region into ring atoms (black), substituent atoms (blue) and“peripheral” atoms (green). (d) Contributions to total MCburied surface by region. (e) Percentage of atoms from each region that makedirect contact with the protein (defined as atoms burying >5 Å2of MC SASA). (f) Average polar/nonpolar ratio for the atoms from each MCregion that make contact with the protein. Error bars are standard deviations; an asterisk(*) indicates that the specified difference is statistically significant using theMann-Whitney U (rank) test (see Methods).
Mentions: The small MCs tended to be almost fully enveloped within their protein bindingsites, burying a quite uniform 82 ± 4 % of their total solvent accessiblesurface area (SASA) upon binding (Figure 3a; Supplementary Table 3), asexemplified by Macbecin in its complex with hsp90 (Figure2c). In contrast, the large MCs appeared to bury a fairly uniform 630 ±120 Å2 of surface upon binding,corresponding to an average of 57 ± 8 % of the compounds’ totalSASA, with at most a modest dependence on MC size. This value is roughly twice the 300± 130 Å2 of SASA buried by a typicaldrug30, and approaches the 800± 200 Å2 of SASA buried on averageby each binding partner at a protein-protein interface31.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry, Boston University, Boston, Massachusetts, USA.

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.

Show MeSH
Related in: MedlinePlus