TY - JOUR
T1 - Fragment-based Shape Signatures
T2 - A new tool for virtual screening and drug discovery
AU - Zauhar, Randy J.
AU - Gianti, Eleonora
AU - Welsh, William J.
N1 - Funding Information:
Acknowledgments We gratefully acknowledge the University City Keystone Innovation Zone for funding to support critical computational work. The authors thank Dr. Christof H. Schwab and Molecular Networks GmbH for providing access to key supporting software. University City Keystone Innovation Zone for funding to support critical computational work.
PY - 2013/12
Y1 - 2013/12
N2 - Since its introduction in 2003, the Shape Signatures method has been successfully applied in a number of drug design projects. Because it uses a ray-tracing approach to directly measure molecular shape and properties (as opposed to relying on chemical structure), it excels at scaffold hopping, and is extraordinarily easy to use. Despite its advantages, a significant drawback of the method has hampered its application to certain classes of problems; namely, when the chemical structures considered are large and contain heterogeneous ring-systems, the method produces descriptors that tend to merely measure the overall size of the molecule, and begin to lose selective power. To remedy this, the approach has been reformulated to automatically decompose compounds into fragments using ring systems as anchors, and to likewise partition the ray-trace in accordance with the fragment assignments. Subsequently, descriptors are generated that are fragment-based, and query and target molecules are compared by mapping query fragments onto target fragments in all ways consistent with the underlying chemical connectivity. This has proven to greatly extend the selective power of the method, while maintaining the ease of use and scaffold-hopping capabilities that characterized the original implementation. In this work, we provide a full conceptual description of the next generation Shape Signatures, and we underline the advantages of the method by discussing its practical applications to ligand-based virtual screening. The new approach can also be applied in receptor-based mode, where protein-binding sites (partitioned into subsites) can be matched against the new fragment-based Shape Signatures descriptors of library compounds.
AB - Since its introduction in 2003, the Shape Signatures method has been successfully applied in a number of drug design projects. Because it uses a ray-tracing approach to directly measure molecular shape and properties (as opposed to relying on chemical structure), it excels at scaffold hopping, and is extraordinarily easy to use. Despite its advantages, a significant drawback of the method has hampered its application to certain classes of problems; namely, when the chemical structures considered are large and contain heterogeneous ring-systems, the method produces descriptors that tend to merely measure the overall size of the molecule, and begin to lose selective power. To remedy this, the approach has been reformulated to automatically decompose compounds into fragments using ring systems as anchors, and to likewise partition the ray-trace in accordance with the fragment assignments. Subsequently, descriptors are generated that are fragment-based, and query and target molecules are compared by mapping query fragments onto target fragments in all ways consistent with the underlying chemical connectivity. This has proven to greatly extend the selective power of the method, while maintaining the ease of use and scaffold-hopping capabilities that characterized the original implementation. In this work, we provide a full conceptual description of the next generation Shape Signatures, and we underline the advantages of the method by discussing its practical applications to ligand-based virtual screening. The new approach can also be applied in receptor-based mode, where protein-binding sites (partitioned into subsites) can be matched against the new fragment-based Shape Signatures descriptors of library compounds.
KW - Fragment-based shape signatures
KW - Ligand-based drug design
KW - Scaffold hopping
KW - Shape signatures
KW - Shape similarity
KW - Virtual screening
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U2 - 10.1007/s10822-013-9698-7
DO - 10.1007/s10822-013-9698-7
M3 - Article
C2 - 24366428
AN - SCOPUS:84891875006
SN - 0920-654X
VL - 27
SP - 1009
EP - 1036
JO - Journal of Computer-Aided Molecular Design
JF - Journal of Computer-Aided Molecular Design
IS - 12
ER -