| Autor: |
Dekker, Frank J, de Mol, Nico J, Bultinck, Patrick, Kemmink, Johan, Hilbers, Hans W, Liskamp, Rob M J, Dekker, Frank |
| Přispěvatelé: |
Biopharmaceuticals, Discovery, Design and Delivery (BDDD), Medicinal Chemistry and Bioanalysis (MCB) |
| Jazyk: |
angličtina |
| Rok vydání: |
2003 |
| Předmět: |
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| Zdroj: |
Bioorganic & Medicinal Chemistry, 11(6), 941-9. PERGAMON-ELSEVIER SCIENCE LTD |
| ISSN: |
0968-0896 |
| Popis: |
A general approach in drug design is making ligands more rigid in order to avoid loss in conformational entropy (deltaS(conf)) upon receptor binding. We hypothesized that in the high affinity binding of pYEEI peptide ligands to the p56(lck) SH2 domain this loss in deltaS(conf) might be diminished due to preorganization of the fourfold negatively charged pYEEI peptide in the bound, extended, conformation. A thermodynamic analysis was performed on the peptides Ac-pYEEI-NH(2), Ac-pYAAI-NH(2) and Ac-pYGGI-NH(2) using surface plasmon resonance (SPR) competition experiments to assay affinity constants at different temperatures. To study the effect of solution conformation and flexibility a computational conformation analysis was performed from which low energy conformations in solution were calculated, and S(conf) estimated. It was found that the calculated low energy conformations for especially the pYE moiety in solution resemble that in the bound state. In the calculated minimum energy conformation in solution isoleucine is bent towards the pY aromatic ring, the occurrence of such conformation is experimentally confirmed by NMR. The estimated values for S(conf) of the EE- and AA-peptide were similar, suggesting no predominant role of preorganization of the solution conformation due to electrostatic repulsion. Apparently the thermodynamics obey the same entropy-enthalpy compensation relationship, which also was found to hold for other peptides and peptidomimetics binding to p60(src) family SH2 domains. The implications of the results for drug design are discussed. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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