Virtual structure based

As long as the virtual structure-based screening procedure identifies compound proposals that can be realized and tested in a short period of time, the accuracy lacking in the scoring functions can be compensated and finally validated by the biophysical screening experiment itself. 

Both ligand- and structure-based methods can be applied in virtual screening. An example of a workflow chart for virtual screening is depicted in Figure 10,4-3. 

Table 10.4-5. Recent successes of structure-based virtual screening approaches.

Barril X, Hubbard RE, Morley SD. Virtual screening in structure-based drug discovery. Mini Rev Med Chem. 2004 4 779-91. 

Schulz-Gasch T, Stahl M. Binding site characteristics in structure-based virtual screening evaluation of current docking tools. J Mol Model 2003 9 47-57. 

Good A. Structure-based virtual screening protocols. Curr Opin Drug Discov Dev 2001 4 301-7. 

Waszkowycz B. Structure-based approaches to drug design and virtual screening. Curr Opin Drug Discov Dev 2002 5 407-13. 

Lyne PD. Structure-based virtual screening an overview. Drug Discov Today 2002 7 1047-55. 

Flohr S, Kurz M, Kostenis E, Brkovich A, Fournier A, Klabunde T. Identification of nonpeptidic urotensin II receptor antagonists by virtual screening based on a pharmacophore model derived from structure-activity relationships and nuclear magnetic resonance studies on urotensin II. J Med Ghent 2002 45 1799-805. 

Stahl M. Structure-based library design. In Bohm HJ, Schneider G, editors. Virtual screening for bioactive molecules (Vol. 10 of Mannhold R, Kubinyi H, Timmerman H, editors. Methods and principles in medicinal chemistry). Wein-heim Wiley-VCH, 2000, pp. 229-64. 

Brenk R, Meyer EA, Reuter K, Stubbs MT, Garcia GA, Diederich E, Klebe G. Crystallographic study of inhibitors of tRNA-guanine transglycosylase snggests a new structure-based pharmacophore for virtual screening. J Mol Biol 2004 338 55-75. 

G, Jiang H, Chen K. Structure-based discovery of potassium channel blockers from natural products virtual screening and electrophysiological assay testing. Chem Biol 2003 10 1103-13. 

Filikov AV, Mohan V, Vickers TA, Griffey RH, Cook PD, Abagyan RA, James TL. Identification of ligands for RNA targets via structure-based virtual screening HIV-1 TAR. / Comput Aided Mol Design 2000 14 593-610. 

Keywords VS, Virtual Screening, Lead discovery, lead, HTS, Pharmacophore-Based, Structure-Based, Fragment-based, Ligand-based, Docking, Scoring, hybrid workflows, VS strategy, Benchmarking VS... 

PF1BVS Pharmacophore-based virtual screening SBVS (Protein) Structure-based virtual screening... 

It is particularly effective to pair structure-based design with array synthesis. A relatively larger virtual library of possible analogs can be docked into the structure and the analogs prioritized for synthesis or eliminated if scored low. 

A virtual screen of 10,000 primary amine fragments against dipeptidyl peptidase IV (a diabetes target) identified a number of hits, as determined by bioassay screening at 100 pM, e.g. 6 [21]. An X-ray structure of this fragment confirmed the predicted binding mode in the Si pocket and inspired a structure-based hypothesis that eventually led to identification of a potent series of DPP-IV inhibitors [22],... 

Molecular docking (structure-based virtual screening) on the basis of a target protein structure, ligand molecules that bind to the active site of the target are searched for. 

Fig. 4.1 Virtual screening tools can be categorized by the compound data to be screened (compound collection, combinatorial library, chemistry space) and the query type (structure-based, ligand-based, descriptor-based, pharmacophore-based). The output is always a list of compounds together with a score quantifying the fit to the query.

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