TY - JOUR
T1 - Comparison of experimental and computational functional group mapping of an RNase A structure
T2 - Implications for computer-aided drug design
AU - Joseph-McCarthy, Diane
AU - Fedorov, Alexander A.
AU - Almo, Steven C.
N1 - Funding Information:
We thank Martin Karplus for providing MCSS and James M.Hogle for use of his computer facilities. This work was supported in part by a Radcliffe Bunting Institute Science Scholars Fellowship to D.J.-M. and grants from NIH (GM 50121) and the W.M.Keck Foundation to S.C.A.
PY - 1996/9
Y1 - 1996/9
N2 - One relatively new computational approach to the drug discovery process involves calculating functional group maps of a target structure. Experimental functional group mapping techniques have also recently emerged. In this paper, the structure of RNase A with two bound formates (i.e. carboxylate functionalities) is used as a model system to test the computational methodology. Functional group maps of the RNase A structure were calculated using the Multiple Copy Simultaneous Search (MCSS) method and compared with experimentally determined formate and water positions. The calculations indicate that the protonation state of active-site histidines determines the ability of the enzyme to bind formate. The results also suggest an ordered binding mechanism for the two formates. An improved strategy for using the MCSS method to design new candidate ligands is discussed.
AB - One relatively new computational approach to the drug discovery process involves calculating functional group maps of a target structure. Experimental functional group mapping techniques have also recently emerged. In this paper, the structure of RNase A with two bound formates (i.e. carboxylate functionalities) is used as a model system to test the computational methodology. Functional group maps of the RNase A structure were calculated using the Multiple Copy Simultaneous Search (MCSS) method and compared with experimentally determined formate and water positions. The calculations indicate that the protonation state of active-site histidines determines the ability of the enzyme to bind formate. The results also suggest an ordered binding mechanism for the two formates. An improved strategy for using the MCSS method to design new candidate ligands is discussed.
KW - Computational drug design
KW - Functional group mapping
KW - Multiple Copy Simultaneous Search (MCSS)
KW - RNase A
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U2 - 10.1093/protein/9.9.773
DO - 10.1093/protein/9.9.773
M3 - Article
C2 - 8888143
AN - SCOPUS:0029796290
VL - 9
SP - 773
EP - 780
JO - Protein Engineering, Design and Selection
JF - Protein Engineering, Design and Selection
SN - 1741-0126
IS - 9
ER -