3D database searches

D database searching. As each conformation is generated an appropriate bit is set in the binary key. At me, the binary key appropriate to the pharmacophore is set up and compared with the keys in the database. 

A flow chart showing the various phases leading to the final compound is reproduced ii Figure 12.35. The first step was a 3D database search of a subset of the Cambridge Structura Database. The pharmacophore for this search comprised two hydrophobic groups and i... 

H-J 1998. Prediction of Binding Constants of Protein Ligands A Fast Method for the aritisation of Hits Obtained from De Novo Design or 3D Database Search Programs. Journal of nputer-Aided Molecular Design 12 309-323. 

Martin YC. 3D database searching in drug design. J Med Chem 1992 35 2145-54. 

Iwata Y, Arisawa M, Hamada R, Kita Y, Mizutani MY, Tomioka N, Itai A, Miyamoto S. Discovery of novel aldose reductase inhibitors using a protein structure-based approach 3D-database search followed by design and synthesis. J Med Chem 2001 44 1718-28. 

The standard screening approach when several active molecules have been identified is pharmacophore mapping followed by 3D database searching. This approach assumes that the active molecules have a common mode of action and that features that are common to all of the molecules describe the pharmacophoric pattern responsible for the observed bioactivity. This is a powerful technique but one that may not be applicable to the structurally heterogeneous hits that characterize typical HTS experiments or sets of competitor compounds drawn from the public literature. In such cases, it is appropriate to consider approaches based on 2D similarity searching and we present here a comparison of approaches for combining the structural information that can be gleaned from a small set of reference structures. 

Alternatively, Giiner and Henry (14) have introduced the G-H score, which is a weighted average of recall and precision. The score was originally developed for evaluating the effectiveness of three-dimensional (3D) database searches but can be applied to the evaluation of any sort of search for which qualitative bioactivity data are available. Using the previous notation, the G-H score is defined to be... 

Giiner, O. F. and Henry, D. R. Formula for determining the goodness of hit lists in 3D database searches. At URL http //www.netsci.orp/Science/Cheminform/ feature09.html. 

Sadowski, J. (1997) A hybrid approach for addressing ring flexibility in 3D database searching. J Comput Aided Mol Des 11, 53-60. 

NCI-3D database - Search the NCI-3D database of over 126,000 compounds from ChemWeb.com via a substructure, similarity, or exact match query on the chemical structure. 

Novellino E, Cosimelli B, Ehlardo M, Greco G, Iadanza M, Lavecchia A, Rimoli MG, Sala A, Da Settimo A, Primofiore G, Da Settimo F, Taliani S, La Motta C, Klotz KN, Tuscano D, Trincavelli ML, Martini C (2005) 2-(Benzimidazol-2-yl)quinoxalines a novel class of selective antagonists at human Aj and A3 adenosine receptors designed by 3D database searching. J Med Chem 48 8253-8260... 

Protein Ligands—A Fast Method for the Prioritization of Hits Obtained from De Novo Design or 3D Database Search Programs. 

H-J Bohm (1998) Prediction of binding constants of protein ligands A fast method for the prioritization of hits obtained from de novo design or 3D database search programs, J Comput Aided Mol Design 12(4) 309-323... 

An extension of the method that enables the steric shape of a protein site to be used as an additional constraint in the comparison of multiple potential pharmacophores of a protein site with a ligand has been developed, and is being commercialised as the DiR module of Chem-X. The method is equivalent to simultaneous 3D-database searching using multiple 3D pharmacophoric queries and steric constraints the advantage is that only one conformational sampling is necessary. 

Van Drie, J.H. "Shrink-wrap" Surfaces A New Method for Incorporating Shape into Pharmacophoric 3D Database Searching. J. Chem. Inf. Comput. Sci., 1997, 37, 38-42. 

Use of this particular pharmacophore in subsequent 3D database searching of about 1 million compounds resulted in 244 interesting compounds, from which 19 compounds showed IC50 values below 10 pM. 

Virtual screening (in silico screening, 3D database search) of known compounds... 

The binding models were vahdated according to their coverage (capacity as a three-dimensional (3D) database search queries) and predictive... 

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