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of drug-like molecules, e.g. conformational flexibility of ligand/protein and appropriate
scoring functions, small fragments exhibit relatively weaker affinity and less specificity.
Commercially available fragment libraries are constructed with generally similar object-
ives such as compliant with Astex's rule of three,
[
10
]
yet they exhibit significant differences
in their property distributions. Perhaps more important for fragment library design is the
intended purpose, since solubility requirements can vary greatly for crystallography, NMR
and surface plasmon resonance detection methods. Similarly for virtual screening, frag-
ment databases may be designed with a particular focus. In the examples above, a fragment
database of readily available reagents was transformed
in silico
into synthons, reflecting
how they would be used synthetically to construct larger targeted drug-like molecules. By
utilizing a docked fragment or scaffold in an active site, the difficulty in virtual screening
over available fragments to enhance binding affinity is significantly reduced by permitted
chemistry and also protein-ligand interactions. Virtual screening of fragment libraries is
most successful when the active site is well characterized and the binding modes of the
fragments are constrained. By way of example, both retrospective and prospective virtual
scans of amine fragments identified active BACE-1 compounds that utilized favorable
interactions in the P1
and P3 pockets, respectively. Another critical component for frag-
ment scanning is the availability of good scoring functions, parameterized for each pocket
separately. Although virtual screening of fragments remains a challenging area of research,
success can be achieved through application of both steric constraints in the active site and
synthetic suitability of fragments.
References
[1] Rees D.C., Congreve M., Murray C.W., Carr R., Fragment-based lead discovery.
Nat. Rev. Drug
Discov
. 2004,
3
, 660-672.
[2] Sherman W., Using fragments to couple ligand- and structure-based approaches. Presented at
the ACS Meeting, Boston, MA, 18-23 August 2007.
[3] Abad-Zapatero C., Metz J., Ligand efficiency indices as guideposts for drug discovery.
Drug
Discov. Today
2005,
10
, 464-469.
[4] Hopkins A.L., Groom C.R., Alex A., Ligand efficiency: a useful metric for lead selection.
Drug
Discov. Today
2004,
9
, 430-431.
[5] Warren G.L., Andrews C.W., Capelli A.-M., Clarke B., LaLonde J., Lambert M.H., Lindvall M.,
Nevins N., Semus S.F., Senger S., Tedesco G., Wall I.D., Woolven J.M., Peishoff, C.E., Head
M.S., A critical assessment of docking programs and scoring functions.
J. Med. Chem
. 2006,
49
, 5912-5931.
[6] Sherman W., Schrödinger (personal communication).
[7] Tari L.W., Jennings A.J., McRee D.E., Use of high-throughput crystallography and in silico
methods for structure-based drug design. In
Industrial Proteomics: Applications for Biotech-
nology and Pharmaceuticals
, ed. Figeys D., John Wiley & Sons, Inc., Hoboken, NJ, 2005,
pp. 107-129.
[8] Verheij H.J., Leadlikeness and structural diversity of synthetic screening libraries.
Mol.
Diversity
2006,
10
, 377-388.
[9] Maybridge, Trevillet, Tintagel, Cornwall, http://www.maybridge.com/Images/pdfs/Ro3frag.pdf.
[10] GhoseA.K., Viswanadhan V.N., Wendoloski J.J., Prediction of hydrophobic (lipophilic) proper-
ties of small organic molecules using fragmental methods: an analysis of ALOGP and CLOGP
methods.
J. Phys. Chem. A
1998,
102
, 3762-3772.
