Receptor flexibility in the in silico screening of reagents in the S1' pocket of human collagenase.

Article Details

Citation

Kallblad P, Todorov NP, Willems HM, Alberts IL

Receptor flexibility in the in silico screening of reagents in the S1' pocket of human collagenase.

J Med Chem. 2004 May 20;47(11):2761-7.

PubMed ID
15139754 [ View in PubMed
]
Abstract

A major difficulty in structure-based molecular design is the prediction of the structure of the protein-ligand complex because of the enormous number of degrees of freedom. Commonly, the target protein is kept rigid in a single low-energy conformation. However, this does not reflect the dynamic nature of protein structures. In this work, we investigate the influence of receptor flexibility in virtual screening of reagents on a common scaffold in the S1' pocket of human collagenase (matrix metalloproteinase-1). We compare screening using a single-crystal structure and multiple NMR structures, both apo and holo forms. We also investigate two computational methods of addressing receptor flexibility that can be used when NMR data are not available. The results from virtual screening using the experimental structures are compared to those obtained using the two computational methods. From the results, we draw conclusions about the impact of target flexibility on the identification of active and diverse reagents in a virtual screening protocol.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
[[1-[N-HYDROXY-ACETAMIDYL]-3-METHYL-BUTYL]-CARBONYL-LEUCINYL]-ALANINE ETHYL ESTERInterstitial collagenaseIC 50 (nM)40N/AN/ADetails