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De novo molecular
design and VHTS: A powerful strategy for Drug discovery
Colin
W.G.Fishwick
University of Leeds, School of Chemistry, Leeds, LS2 9JT, UK
Abstract:
In
silico molecular docking techniques such as virtual high-throughput
screening (VHTS), are powerful approaches to the discovery of new
enzyme inhibitors. Additionally, de novo design is a powerful
complementary strategy for inhibitor discovery. Here, by using the
structural features present within the enzyme only, new inhibitor
designs are built-up sequentially according to the requirements of the
targeted binding site. Therefore, de novo design is an important
technique to use in parallel with VHTS in a particular hit
identification campaign, as a good de novo design program will examine
structure space larger by many orders of magnitude than that of most
virtual libraries currently used for this purpose. We have recently
applied both the de novo molecular design computer program SPROUT, and
the VHTS program eHiTS to a number of therapeutically attractive enzyme
targets and have, in the majority of cases under study, rapidly
identified inhibitors in the micromolar range or better.
References
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Besong, J.M Bostock, W. Stubbings, I. Chopra, A.P. Johnson, D.I. Roper,
A.J. Lloyd, and C.W.G. Fishwick. A novel de novo designed inhibitor of
D-ala-D-ala ligase from E.coli. Angew. Chem. Int. Ed. Engl., 2005, 44, 6403 - 6.
- M.A. Ali, N. Bhogal, J.B.C. Findlay, and C.W.G.
Fishwick. The first de novo designed antagonists of the human NK2
receptor. J. Med. Chem, 48, 2005,
5655-58
- T. Heikkila, S. Thrumalairajan, M. Davies, A.P.
Johnson, G. McConkey, and C.W.G. Fishwick. The first de novo designed
inhibitors of plasmodium falciparum dihydroorotate dehydrogenase.
Bioorg. Med. Chem. Lett., 2006,
16, 88-92
- C. Ramsey, C. Galtier, A.M.W. Stead, A.P.
Johnson, T. Heikilla, M. Davies, C.W.G. Fishwick, A.N. Boa, and
G. McConkey. J. Med. Chem., 2007,
50, 186 – 191.
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