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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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MC Binding Modes. (a) Edge-on binding mode, as exemplified bycyclosporin (Csp) binding to cyclophilin. MCs that bind edge-on typically adopt aconformation in which the ring is flattened and elongated, such that even substituentsattached to the solvent-exposed edge of the ring can reach to make extensive contact withthe protein. (b) Face-on binding mode, exemplified by the binding ofPectenotoxin-2 to actin. MCs that bind face-on typically project a large substituent intoa substantial neighboring pocket or cleft. (c) Compact binding mode observedfor most of the small MCs, exemplified by Macbecin bound to hsp90. Upper panel shows theconformation of the ligand (red) when bound to its protein target (wheat). The imagesbelow show surface representations of the MC ligands from the upper panels, viewed lookingdown on the exposed portion of the compound (upper image) and from the side (lower image),with the ligand atoms color-coded according to how much contact they make with the protein(Red ≥ 90% buried, orange = 50–90 % buried, Yellow =25–50% buried, and White = <25% buried).
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Figure 2: MC Binding Modes. (a) Edge-on binding mode, as exemplified bycyclosporin (Csp) binding to cyclophilin. MCs that bind edge-on typically adopt aconformation in which the ring is flattened and elongated, such that even substituentsattached to the solvent-exposed edge of the ring can reach to make extensive contact withthe protein. (b) Face-on binding mode, exemplified by the binding ofPectenotoxin-2 to actin. MCs that bind face-on typically project a large substituent intoa substantial neighboring pocket or cleft. (c) Compact binding mode observedfor most of the small MCs, exemplified by Macbecin bound to hsp90. Upper panel shows theconformation of the ligand (red) when bound to its protein target (wheat). The imagesbelow show surface representations of the MC ligands from the upper panels, viewed lookingdown on the exposed portion of the compound (upper image) and from the side (lower image),with the ligand atoms color-coded according to how much contact they make with the protein(Red ≥ 90% buried, orange = 50–90 % buried, Yellow =25–50% buried, and White = <25% buried).

Mentions: The MC-protein binding modes observed among the test set can be described interms of three broadly distinct interaction geometries. Slightly more than half of thelarge MCs bind with the MC ring roughly perpendicular to the protein surface, such thatone edge of the ring binds along the bottom of an extended groove or cleft on the protein,with substituents interacting with adjacent binding pockets, and the outer edge of thering exposed to solvent. An example of this “edge-on” binding mode isshown in Figure 2a. The remaining large MCs adopt adifferent binding geometry in which the MC ring lies face-on to the protein surface,making contacts across a large area (Figure 2b). TheMCs that display this face-on binding mode invariably have 1–2 large substituentsthat interact with substantial adjacent clefts or pockets on the protein. In contrast,most of the small MCs adopt a compact, roughly globular conformation and bind in a cleftor pronounced depression on the protein (Figure2c).


How proteins bind macrocycles.

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

MC Binding Modes. (a) Edge-on binding mode, as exemplified bycyclosporin (Csp) binding to cyclophilin. MCs that bind edge-on typically adopt aconformation in which the ring is flattened and elongated, such that even substituentsattached to the solvent-exposed edge of the ring can reach to make extensive contact withthe protein. (b) Face-on binding mode, exemplified by the binding ofPectenotoxin-2 to actin. MCs that bind face-on typically project a large substituent intoa substantial neighboring pocket or cleft. (c) Compact binding mode observedfor most of the small MCs, exemplified by Macbecin bound to hsp90. Upper panel shows theconformation of the ligand (red) when bound to its protein target (wheat). The imagesbelow show surface representations of the MC ligands from the upper panels, viewed lookingdown on the exposed portion of the compound (upper image) and from the side (lower image),with the ligand atoms color-coded according to how much contact they make with the protein(Red ≥ 90% buried, orange = 50–90 % buried, Yellow =25–50% buried, and White = <25% buried).
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Related In: Results  -  Collection

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Figure 2: MC Binding Modes. (a) Edge-on binding mode, as exemplified bycyclosporin (Csp) binding to cyclophilin. MCs that bind edge-on typically adopt aconformation in which the ring is flattened and elongated, such that even substituentsattached to the solvent-exposed edge of the ring can reach to make extensive contact withthe protein. (b) Face-on binding mode, exemplified by the binding ofPectenotoxin-2 to actin. MCs that bind face-on typically project a large substituent intoa substantial neighboring pocket or cleft. (c) Compact binding mode observedfor most of the small MCs, exemplified by Macbecin bound to hsp90. Upper panel shows theconformation of the ligand (red) when bound to its protein target (wheat). The imagesbelow show surface representations of the MC ligands from the upper panels, viewed lookingdown on the exposed portion of the compound (upper image) and from the side (lower image),with the ligand atoms color-coded according to how much contact they make with the protein(Red ≥ 90% buried, orange = 50–90 % buried, Yellow =25–50% buried, and White = <25% buried).
Mentions: The MC-protein binding modes observed among the test set can be described interms of three broadly distinct interaction geometries. Slightly more than half of thelarge MCs bind with the MC ring roughly perpendicular to the protein surface, such thatone edge of the ring binds along the bottom of an extended groove or cleft on the protein,with substituents interacting with adjacent binding pockets, and the outer edge of thering exposed to solvent. An example of this “edge-on” binding mode isshown in Figure 2a. The remaining large MCs adopt adifferent binding geometry in which the MC ring lies face-on to the protein surface,making contacts across a large area (Figure 2b). TheMCs that display this face-on binding mode invariably have 1–2 large substituentsthat interact with substantial adjacent clefts or pockets on the protein. In contrast,most of the small MCs adopt a compact, roughly globular conformation and bind in a cleftor pronounced depression on the protein (Figure2c).

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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