scholarly journals Structure-Based Design of a Macrocyclic PROTAC

2019 ◽  
Author(s):  
Andrea Testa ◽  
Scott J. Hughes ◽  
Xavier Lucas ◽  
Jane E. Wright ◽  
Alessio Ciulli
Keyword(s):  
Crystal Structure ◽  
Rational Design ◽  
Enzyme Inhibitors ◽  
Protein Complexes ◽  
Linear Molecule ◽  
Chemical Probes ◽  
Bifunctional Molecules ◽  
Design And Synthesis ◽  
Biophysical Studies ◽  
New Interactions

Constraining a molecule in its bioactive conformation via macrocyclization represents an attractive strategy to rationally design functional chemical probes. While this approach has been applied to design enzyme inhibitors or receptor antagonists, to date it remains unprecedented for bifunctional molecules that bring proteins together, such as PROTAC degraders. Here, we report the design and synthesis of a first macrocyclic PROTAC based on co-crystal structure of a parent linear molecule, by adding a cyclizing linker. A co-crystal structure of the macrocyclic PROTAC bound in a ternary complex with VHL and Brd4 validated the rational design and identified new interactions formed by the new linker. Biophysical studies revealed that the macrocycle selectively discriminated the second against the first bromodomains of BET proteins, and is a potent Brd4 degrader. Macrocyclization provides a viable strategy to induce protein-protein complexes and protein degradation inside cells.

scholarly journals Structure-Based Design of a Macrocyclic PROTAC

2019 ◽  
Author(s):  
Andrea Testa ◽  
Scott J. Hughes ◽  
Xavier Lucas ◽  
Jane E. Wright ◽  
Alessio Ciulli
Keyword(s):  
Crystal Structure ◽  
Rational Design ◽  
Ternary Complex ◽  
Enzyme Inhibitors ◽  
Cellular Activity ◽  
Chemical Probes ◽  
Bioactive Conformation ◽  
Bifunctional Molecules ◽  
Design And Synthesis ◽  
Biophysical Studies

Constraining a molecule in its bioactive conformation via macrocyclization represents an attractive strategy to rationally design functional chemical probes. While this approach has been applied to enzyme inhibitors or receptor antagonists, to date it remains unprecedented for bifunctional molecules that bring proteins together, such as PROTAC degraders. Here, we report the design and synthesis of a first macrocyclic PROTAC by adding a second cyclizing linker to the BET degrader MZ1. A co-crystal structure of macroPROTAC-1 bound in a ternary complex with VHL and the second Brd4 bromodomain validated the rational design. Biophysical studies revealed enhanced discrimination between the second and the first bromodomains of BET proteins. Despite a 12-fold loss of binary binding affinity for Brd4, macroPROTAC-1 exhibited cellular activity comparable to MZ1. Our findings support macrocyclization as an advantageous strategy to enhance PROTAC degradation potency and selectivity between homologous targets.

scholarly journals Structure-Based Design of a Macrocyclic PROTAC

2019 ◽  
Author(s):  
Andrea Testa ◽  
Scott J. Hughes ◽  
Xavier Lucas ◽  
Jane E. Wright ◽  
Alessio Ciulli
Keyword(s):  
Crystal Structure ◽  
Rational Design ◽  
Ternary Complex ◽  
Enzyme Inhibitors ◽  
Cellular Activity ◽  
Chemical Probes ◽  
Bioactive Conformation ◽  
Bifunctional Molecules ◽  
Design And Synthesis ◽  
Biophysical Studies

Constraining a molecule in its bioactive conformation via macrocyclization represents an attractive strategy to rationally design functional chemical probes. While this approach has been applied to enzyme inhibitors or receptor antagonists, to date it remains unprecedented for bifunctional molecules that bring proteins together, such as PROTAC degraders. Here, we report the design and synthesis of a first macrocyclic PROTAC by adding a second cyclizing linker to the BET degrader MZ1. A co-crystal structure of macroPROTAC-1 bound in a ternary complex with VHL and the second Brd4 bromodomain validated the rational design. Biophysical studies revealed enhanced discrimination between the second and the first bromodomains of BET proteins. Despite a 12-fold loss of binary binding affinity for Brd4, macroPROTAC-1 exhibited cellular activity comparable to MZ1. Our findings support macrocyclization as an advantageous strategy to enhance PROTAC degradation potency and selectivity between homologous targets.

Design and synthesis of new enzymes based on the lactate dehydrogenase framework

1991 ◽  
Vol 332 (1263) ◽  
pp. 177-184 ◽  
Keyword(s):  
Crystal Structure ◽  
Lactate Dehydrogenase ◽  
Malate Dehydrogenase ◽  
Functional Groups ◽  
Maximum Rate ◽  
Chemical Probes ◽  
Protein Surface ◽  
Design And Synthesis ◽  
Tryptophan Residues ◽  
Lactate Dehydrogenases

Analysis of the mechanism and structure of lactate dehydrogenases is summarized in a map of the catalytic pathway. Chemical probes, single tryptophan residues inserted at specific sites and a crystal structure reveal slow movements of the protein framework that discriminate between closely related small substrates. Only small and correctly charged substrates allow the protein to engulf the substrate in an internal vacuole that is isolated from solvent protons, in which water is frozen and hydride transfer is rapid. The closed vacuole is very sensitive to the size and charge of the substrate and provides discrimination between small substrates that otherwise have too few functional groups to be distinguished at a solvated protein surface. This model was tested against its ability to successfully predict the design and synthesis of new enzymes such as L-hydroxyisocaproate dehydrogenase and fully active malate dehydrogenase. Solvent friction limits the rate of forming the vacuole and thus the maximum rate of catalysis.

scholarly journals Rational Design and Synthesis of Right-Handed d-Sulfono-γ-AApeptide Helical Foldamers as Potent Inhibitors of Protein–Protein Interactions

2020 ◽  
Vol 85 (16) ◽  
pp. 10552-10560
Author(s):  
Peng Sang ◽  
Yan Shi ◽  
Pirada Higbee ◽  
Minghui Wang ◽  
Sami Abdulkadir ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Rational Design ◽  
Protein Protein Interactions ◽  
Design And Synthesis

Rational design and crystal structure prediction of ring-fused double-PDI compounds as n-channel organic semiconductors: a DFT study

2021 ◽  
Author(s):  
Suryakanti Debata ◽  
Smruti R. Sahoo ◽  
Rudranarayan Khatua ◽  
Sridhar Sahu
Keyword(s):  
Crystal Structure ◽  
Charge Transport ◽  
Organic Semiconductors ◽  
Structure Prediction ◽  
Rational Design ◽  
Molecular Design ◽  
Design Strategy ◽  
Dft Study ◽  
Crystal Structure Prediction ◽  
Model Compounds

In this study, we present an effective molecular design strategy to develop the n-type charge transport characteristics in organic semiconductors, using ring-fused double perylene diimides (DPDIs) as the model compounds.

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