Abstract
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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 773-780 |
| Number of pages | 8 |
| Journal | Protein Engineering |
| Volume | 9 |
| Issue number | 9 |
| State | Published - Sep 1996 |
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Keywords
- Computational drug design
- Functional group mapping
- Multiple Copy Simultaneous Search (MCSS)
- RNase A
ASJC Scopus subject areas
- Molecular Biology
- Biochemistry
Cite this
Comparison of experimental and computational functional group mapping of an RNase A structure : Implications for computer-aided drug design. / Joseph-McCarthy, Diane; Fedorov, Alexander A.; Almo, Steven C.
In: Protein Engineering, Vol. 9, No. 9, 09.1996, p. 773-780.Research output: Contribution to journal › Article
}
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.
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
UR - http://www.scopus.com/inward/record.url?scp=0029796290&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0029796290&partnerID=8YFLogxK
M3 - Article
VL - 9
SP - 773
EP - 780
JO - Protein Engineering, Design and Selection
JF - Protein Engineering, Design and Selection
SN - 1741-0126
IS - 9
ER -