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A series of potent CREBBP bromodomain ligands reveals an induced-fit pocket stabilized by a cation-? interaction.

ABSTRACT: The benzoxazinone and dihydroquinoxalinone fragments were employed as novel acetyl lysine mimics in the development of CREBBP bromodomain ligands. While the benzoxazinone series showed low affinity for the CREBBP bromodomain, expansion of the dihydroquinoxalinone series resulted in the first potent inhibitors of a bromodomain outside the BET family. Structural and computational studies reveal that an internal hydrogen bond stabilizes the protein-bound conformation of the dihydroquinoxalinone series. The side chain of this series binds in an induced-fit pocket forming a cation-? interaction with R1173 of CREBBP. The most potent compound inhibits binding of CREBBP to chromatin in U2OS cells.

SUBMITTER: Rooney TP

PROVIDER: S-EPMC4298791 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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A series of potent CREBBP bromodomain ligands reveals an induced-fit pocket stabilized by a cation-π interaction.

Rooney Timothy P C TP Filippakopoulos Panagis P Fedorov Oleg O Picaud Sarah S Cortopassi Wilian A WA Hay Duncan A DA Martin Sarah S Tumber Anthony A Rogers Catherine M CM Philpott Martin M Wang Minghua M Thompson Amber L AL Heightman Tom D TD Pryde David C DC Cook Andrew A Paton Robert S RS Müller Susanne S Knapp Stefan S Brennan Paul E PE Conway Stuart J SJ

Angewandte Chemie (International ed. in English) 20140512 24

The benzoxazinone and dihydroquinoxalinone fragments were employed as novel acetyl lysine mimics in the development of CREBBP bromodomain ligands. While the benzoxazinone series showed low affinity for the CREBBP bromodomain, expansion of the dihydroquinoxalinone series resulted in the first potent inhibitors of a bromodomain outside the BET family. Structural and computational studies reveal that an internal hydrogen bond stabilizes the protein-bound conformation of the dihydroquinoxalinone ser ...[more]

PMID: 24821300

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Project description:The design of ligands with high affinity and specificity remains a fundamental challenge in understanding molecular recognition and developing therapeutic interventions. Charge optimization theory addresses this problem by determining ligand charge distributions that produce the most favorable electrostatic contribution to the binding free energy. The theory has been applied to the design of binding specificity as well. However, the formulations described only treat a rigid ligand-one that does not change conformation upon binding. Here, we extend the theory to treat induced-fit ligands for which the unbound ligand conformation may differ from the bound conformation. We develop a thermodynamic pathway analysis for binding contributions relevant to the theory, and we illustrate application of the theory using HIV-1 protease with our previously designed and validated subnanomolar inhibitor. Direct application of rigid charge optimization approaches to nonrigid cases leads to very favorable intramolecular electrostatic interactions that are physically unreasonable, and analysis shows the ligand charge distribution massively stabilizes the preconformed (bound) conformation over the unbound. After analyzing this case, we provide a treatment for the induced-fit ligand charge optimization problem that produces physically realistic results. The key factor is introducing the constraint that the free energy of the unbound ligand conformation be lower or equal to that of the preconformed ligand structure, which corresponds to the notion that the unbound structure is the ground unbound state. Results not only demonstrate the applicability of this methodology to discovering optimized charge distributions in an induced-fit model, but also provide some insights into the energetic consequences of ligand conformational change on binding. Specifically, the results show that, from an electrostatic perspective, induced-fit binding is not an adaptation designed to enhance binding affinity; at best, it can only achieve the same affinity as optimized rigid binding.

Project description:The chemistry community now recognizes the cation-? interaction as a major force for molecular recognition, joining the hydrophobic effect, the hydrogen bond, and the ion pair in determining macromolecular structure and drug-receptor interactions. This Account provides the author's perspective on the intellectual origins and fundamental nature of the cation-? interaction. Early studies on cyclophanes established that water-soluble, cationic molecules would forego aqueous solvation to enter a hydrophobic cavity if that cavity was lined with ? systems. Important gas phase studies established the fundamental nature of the cation-? interaction. The strength of the cation-? interaction (Li(+) binds to benzene with 38 kcal/mol of binding energy; NH4(+) with 19 kcal/mol) distinguishes it from the weaker polar-? interactions observed in the benzene dimer or water-benzene complexes. In addition to the substantial intrinsic strength of the cation-? interaction in gas phase studies, the cation-? interaction remains energetically significant in aqueous media and under biological conditions. Many studies have shown that cation-? interactions can enhance binding energies by 2-5 kcal/mol, making them competitive with hydrogen bonds and ion pairs in drug-receptor and protein-protein interactions. As with other noncovalent interactions involving aromatic systems, the cation-? interaction includes a substantial electrostatic component. The six (four) C(?-)-H(?+) bond dipoles of a molecule like benzene (ethylene) combine to produce a region of negative electrostatic potential on the face of the ? system. Simple electrostatics facilitate a natural attraction of cations to the surface. The trend for (gas phase) binding energies is Li(+) > Na(+) > K(+) > Rb(+): as the ion gets larger the charge is dispersed over a larger sphere and binding interactions weaken, a classical electrostatic effect. On other hand, polarizability does not define these interactions. Cyclohexane is more polarizable than benzene but a decidedly poorer cation binder. Many studies have documented cation-? interactions in protein structures, where lysine or arginine side chains interact with phenylalanine, tyrosine, or tryptophan. In addition, countless studies have established the importance of the cation-? interaction in a range of biological processes. Our work has focused on molecular neurobiology, and we have shown that neurotransmitters generally use a cation-? interaction to bind to their receptors. We have also shown that many drug-receptor interactions involve cation-? interactions. A cation-? interaction plays a critical role in the binding of nicotine to ACh receptors in the brain, an especially significant case. Other researchers have established important cation-? interactions in the recognition of the "histone code," in terpene biosynthesis, in chemical catalysis, and in many other systems.

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A series of potent CREBBP bromodomain ligands reveals an induced-fit pocket stabilized by a cation-? interaction.

Publications

A series of potent CREBBP bromodomain ligands reveals an induced-fit pocket stabilized by a cation-π interaction.

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