3D Search

In all of the 3D search methods the conformational flexibility creates considerable difficulties. Large databases of multiple conformations for each structure have been developed which make the solution of this problem possible. 

Protein structure know 11 dt novo design, receptor-based 3D searching stnjcture-based design, docking... 

This method represents the most common and traditional application of computational tools to rational drug design. From a list of molecules of known activity, one can establish a 3D-pharmacophore hypothesis that is then transformed into a 3D-search query. This query is then used to search a 3D database for structures that fit the hypothesis within a certain tolerance. If the yield of active molecules is significant, then the query can be used to predict activities on novel compounds. In our situation, the enantiophore is built from the superposition of a list of sample molecules, which are all well separated on a given CSR Hence, the common features of this series of molecules can become a good enantiophore hypothesis for the enantiores-olution on this CSR... 

Starting from a collection of samples remarkably well resolved (alpha > 6) on Chiralcel OD (Cellulose tris(3,5-dimethylphenylcarbamate) coated on aminopropyl silica), a putative three-point enantiophore for binding to CSR was derived (Fig. 4-10). This enantiophore query was used to search (CFS 3D search) within a list comprising 4203 compounds tested on Chiralcel OD. From this search domain of CHIRBASE 3D, 191 structures were found to match the enantiophore. 

In Fig. 4-11, two different samples are displayed in their original conformations and conformations fitted to the query as they are highlighted by the CFS search process. The CFS process rotates single bonds between two atoms to find the maximum and minimum difference possible with the distance and angle constraints. Then, using a torsional fitter, it attempts to minimize in those conformations the deviations between measured values of 3D constraints and the values that are specified in the 3D-search query. 

Muscarinic M3 Receptor. A pharmacophore model was derived from known M3 receptor antagonists, using the program DISCO, and 3D searching was performed by Unity 3D in the Astra Charnwood in-house compound repository and the databases of several commercial suppliers. The 172 compounds that fitted the pharmacophore were screened for their M3-antagonistic potency. Several compounds with micromolar and even submicromolar activities resulted, for example, compound 13 (A50 M3 antagonism 0.2pM pA2 = 6.67 Fig. 16.2) [85],... 

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]. 

An improved 3D pharmacophore, considering all results obtained so far, and a new 3D search in the Aventis compound collection with the program... 

A 3D model of the fibrinogen-derived (very late antigen-4, VLA-4) inhibitor 4-[N -(2-methylphenyl)ureido]phenylacetyl-Leu-Asp-Val was derived from the X-ray structure of the related integrin-binding region of the vascular cell adhesion molecule-1 (VCAM-1). A 3D pharmacophore was generated with the program Catalyst, and a 3D search was performed in 8624 molecules from... 

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In this article, we will restrict ourselves to the case of finding the orientation and position of a known model in another unit cell, to help solve the molecular structure contained in this unit cell (Fig. 7.2). Traditionally, this six-dimensional (6D) search (three orientation angles and three translations are to be found) is divided into two separate and consecutive 3D search problems. 

Jambon M, Andrieu O, Combet C et al (2005) The SuMo server 3D search for protein functional sites. Bioinformatics 21 3929-3930... 

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T. Langer, G. Wolber. Lead optimization pharmacophore definition and 3d searches. Drug Discov. Today, Technol,... 

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Huang YX, Bao YL, Guo SY et al (2008) Pep-3D-Search a method for B-cell epitope prediction based on mimotope analysis. BMC Bioinformatics 9 538... 

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