Use of MCSS to Design Small Targeted Libraries: Application to Picornavirus Ligands
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- 作者：Diane Joseph-McCarthy ; Simon K. Tsang ; David J. Filman ; James M. Hogle ; and Martin Karplus
- 刊名：Journal of the American Chemical Society
- 出版年：2001
- 出版时间：December 26, 2001
- 年：2001
- 卷：123
- 期：51
- 页码：12758 - 12769
- 全文大小：1401K
- 年卷期：v.123,no.51(December 26, 2001)
- ISSN：1520-5126
文摘
Computational methods were used to design structure-based combinatorial libraries of antipicornaviralcapsid-binding ligands. The multiple copy simultaneous search (MCSS) program was employed to calculatefunctionality maps for many diverse functional groups for both the poliovirus and rhinovirus capsid structuresin the region of the known drug binding pocket. Based on the results of the MCSS calculations, smallcombinatorial libraries consisting of 10s or 100s of three-monomer compounds were designed and synthesized.Ligand binding was demonstrated by a noncell-based mass spectrometric assay, a functional immuno-precipitation assay, and crystallographic analysis of the complexes of the virus with two of the candidateligands. The P1/Mahoney poliovirus strain was used in the experimental studies. A comparison showed thatthe MCSS calculations had correctly identified the observed binding site for all three monomer units in oneligand and for two out of three in the other ligand. The correct central monomer position in the second ligandwas reproduced in calculations in which the several key residues lining the pocket were allowed to move. Thisstudy validates the computational methodology. It also illustrates that subtle changes in protein structure canlead to differences in docking results and points to the importance of including target flexibility, as well asligand flexibility, in the design process.