Virtual screening leads

A range of thiolactones was obtained by virtual screening with the rationale to be covalently cleaved by FabDSer92. Among them, 4 was described as a potent E. coli FabD inhibitor with antibiotic properties although no further biological data was provided [12]. 

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

Stahura, F.L., Himeno, T, Shiojiri, S., Kogami, Y, Kouji, H., and Bajorath, J. (2007) Virtual screening leads to the discovery of an effective antagonist of... 

X-ray analysis of a ligand complex led to the discovery of a new, unexpected binding mode 150 involving a main-chain peptide flip, and a water molecule. This observation was then exploited to define a new pharmacophore for virtual screening, leading to the identification of novel sub-micromolar inhibitors. 

Figure 10.4-3. Work flow for virtual screening, from data preparation to finding new leads.

Prediction of various physicochemical properties such as solubihty, lipophhicity log P, pfQ, number of H-donor and acceptor atoms, number of rotatable bonds, polar surface area), drug-likeness, lead-likeness, and pharmacokinetic properties (ADMET profile). These properties can be applied as a filter in the prescreening step in virtual screening. 

Wilton DJ, Willett P, Mullier G, Lawson K. Comparison of ranking methods for virtual screening in lead-discovery programmes. J Chem Inf Comput Sci 2003 43 469-74. 

NMR 3D structure of the undecapeptide U-II generated a ligand pharmacophore hypothesis that served as query for the virtual screening of the Aventis in-house compound repository. Active leads from six different chemical classes could be identihed by the 3D search, for example, compound 17 (ECso = 400nM Fig. 16.2) [91]. 

Langer T, Hoffmann RD. Virtual screening an effective tool for lead structure discovery Curr Pharm Des 2001 7 509-27. 

Oprea TI, Matter H. Integrating virtual screening in lead discovery. Curr Opin Chem Biol 2004 8 349-358. 

Molecules in real solvents can exist in one or more tautomeric forms. The use of different tautomers in calculations can lead to significant variation in the estimated log P values (Pig. 15.1). Accurate prediction of the dominant tautomer requires ah initio calculahons. Due to speed limitations such calculations are not feasible for virtual screening and prediction of large compound collections. Moreover, the interpretation of the results can also be difficult, for example, the lacton-lactim (Pig. 15. IB) is the stable form of maleic hydrazide in the gas phase but the difference between this and the dilacton form (Pig. 15.1C and D) disappears in solution... 

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