Similar shape searches

The USR (Ultrafast Shape Recognition) Method. This method was reported by Ballester and Richards (53) for compound database search on the basis of molecular shape similarity. It was reportedly capable of screening billions of compounds for similar shapes on a single computer. The method is based on the notion that the relative position of the atoms in a molecule is completely determined by inter-atomic distances. Instead of using all inter-atomic distances, USR uses a subset of distances, reducing the computational costs. Specifically, the distances between all atoms of a molecule to each of four strategic points are calculated. Each set of distances forms a distribution, and the three moments (mean, variance, and skewness) of the four distributions are calculated. Thus, for each molecule, 12 USR descriptors are calculated. The inverse of the translated and scaled Manhattan distance between two shape descriptors is used to measure the similarity between the two molecules. A value of 1 corresponds to maximum similarity and a value of 0 corresponds to minimum similarity. 

ROCS is using a shape-based superposition for identifying compounds that have similar shape. Grant and Pickup (118) showed that using atomic-centered Gaussians instead of a spherical function can dramatically reduce the time required for a shape alignment of two molecules. This improved routine allows the program to perform shape-based database searches at an acceptable speed (300-400 conformers/s). 

Two factors contribute to the difficulty of searching 3D databases. First is the difficulty in specifying the search parameters. How are similar shapes defined Second, although the conformation stored in the database may be the most probable conformation (either the crystal structure or an energy minimum), in some cases a higher energy conformation is the biologically active one. Therefore, conformational flexibility should be included in the search process.Different methods have been developed to carry out searches in three dimensions. Detailed introductions to the problems and methods of 3D... 

Because the system is meant to be used for a variety of heat exchangers we could not use a simple (ANN) classifier, but we chose for a CBR type system. The case-base stores signal shapes with corresponding classifications or actions to be taken (e.g. signal mixing). Beftxe each inspection the case-base is filled with data from calibration pipes oc a case-base from a previous similar inspection can be used. For each new possible defect signal a search is done in the case base for the most similar case. 

Andrews KM, Cramer RD. Toward general methods of targeted library design topomer shape similarity searching with diverse structures as queries. / Med Chem 2000 43 1723-40. 

Experimental screening established that compound 42 shown in Fig. 8.11 disrupts ZipA-FtsZ protein-protein interaction. However, previous studies suggested potential issues with toxicity associated with this class of compounds. Additionally such amine-substituted pyridyl-pyrimidines are heavily patented in the context of kinase inhibition. Both of these factors limit the scope of the subsequent lead optimization process, to transform this compound into a viable drug. Knowledge that compound 42 was a micromolar inhibitor of ZipA-FtsZ was exploited by searching for molecules that were similar in shape. 

Fig. 8.11 The molecular structures of 42 and 43. Compound 43 was identified by searching a multiconformational database for molecules that were similar in shape to 42.

Chemical Information, Irvine CA Tripos, Inc. St. Louis MO), similarity searching can be carried out around a well-defined compound class using local descriptors such as atom pairs [46, 47] or topomeric shape [48, 49]. Also, ligand-based pharmacophore searches are able to identify follow-up compounds that are less obvious and more diverse than similarity searches [30, 50-54]. The problem with the latter methods is defining the molecular shape or pharmacophore specifically enough to be useful when there are few hits within a compound class and they cannot be reliably aligned (as is often the case for NMR hits in the absence of detailed structural information). 

Cramer, R.D., Poss, M.A., Hermsmeier, M.A., Caulfield, T.J., and Kowala, M.C. Prospective identification of biologically active structures by topomer shape similarity searching. /. Med. Chem. 

In search for true equilibrium shapes, a smaller system with a periodic length equal to 100 fl is used to study isolated islands. In Fig. 5, such isolated islands are examined as a function ofmisfit strain, e. All other input conditions are similar to those ofFig. 3. Whene = 0, the island becomes a semi-circle in the infinite-torque condition, whereas a lense shape with a dihedral angle of 120° should be established in the zero-torque condition. Albeit some facetting due to the discrete nature, the shapes are consistent with the Wulff construction. For 8 0, the shapes of e = 0 are used as the initial configurations. As e increases, the... 

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