Scaffold-hopping Potential

Retrospective screening was performed in the same manner as by Fechner et al. [33], leaving out the two very general classes GPCR and nuclear receptors. The average enrichment factors for the first 5% of the database are shown in Fig. 3.5. 

As stated previously for the topological CATS descriptor [31], the influence of different similarity metrics on the overall enrichment is marginal. For the full 

The mutual complementation of the different methods was examined in more detail for four selected molecules rofecoxib (COX-2), celecoxib (COX-2), indinavir (HIV protease), and lanepitant (neurokinin receptor). The results are shown in the form of Euler-Venn diagrams in Fig. 3.7. Apparently the methods complement each other. Each method was able to retrieve actives which were not found by the other methods. Interestingly, the performance of the different descriptors varied significantly within one class of ligands (compare, e.g., rofecoxib and celecoxib). 

68 3 Alignment-free Pharmacophore Patterns - A Correlation-vector Approach 

We recently applied CATS3D similarity searching to find novel metabotropic glutamate receptor 5 (mGluR5) modulators. This resulted in eight out of 29 experimentally tested molecules with a Kt below 50 pM [55]. All hits showed different scaffolds compared with the reference molecules. 

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In a recent study on the scaffold-hopping potential of fragment-based de novo design, among ACE inhibitors known lead structures 397b and... 

Renner, S. and Schneider, G. (2006) Scaffold-hopping potential of ligand-based similarity concepts. ChemMedChem, 1, 181-185. 

A further important option for ligand-based virtual screening is to perform shape comparisons that have a pronounced scaffold hopping potential. An often used method of this kind is ROCS [31] (OpenEye Scientific Sofiware, 9 Bisbee Court Suite D, Santa Fe, NM 87508, USA. Available at http //www.eyesopen.com, March 20, 2009). ROCS employs continuous functions that are derived from atom-centered Gaussians to calculate the volume overlap between two 3D structures. The use of Gaussians drastically speeds up the computational process, and ROCS is able to search even databases with millions of compounds for molecules that can adopt shapes similar to the reference compound. As in the case of 3D pharmacophore searches, the low-energy conformations must be precomputed for the search database. 

The simplest way to compare the performance of different descriptors is to perform a retrospective study and to count the numbers of true actives found in different virtual screening hit lists of predefined size and compare them with the hit rate in the search database (enrichment). Enrichment factors, however, are not sufficient to assess the scaffold hopping potential of a descriptor or a search method. 

IkB kinase-p is a key regulatory enzyme in the NF-kB pathway, and inhibition of this enzyme has the potential for yielding treatments for inflammatory and autoimmune diseases. Morwick et al. [53] report on the optimization of a pM IKKp inhibitor with low aqueous solubility, moderate human liver microsome stability, and inhibition of several CYPs (3A4, 2C9, 1A2) with pM potencies. Modulation of the thiophene core (other thiophene isomer, pyrimidine and oxazole) produces compounds of similar potency to the hit. Fusing the 5-phenyl moiety to the thiophene to form a thieno[2,3-b]pyridine core increases aqueous solubility of the series as well as reduces the CYP liability. While the optimized compound still shows pM IKK(S potency, the aqueous solubility, HLM stability and CYP profiles are much improved. A pharmacophore model was generated that enabled scaffold hopping to yield this new chemotype (Scheme 7). 

Low approval rates of new chemical entities by national and international drug administrations and an increasing awareness and measurability of potential side effects of marketed drugs suggest that scaffold hopping and bioisosteric... 

The results of this study demonstrate the potential utility of scaffold hopping approach in designing new antitubercular analogs of carbazole with appended... 

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