Scaffold-hopping

The concept of scaffold hopping invokes the use of computational tools that when given a reference structure can propose a different structure likely to have similar biological properties. A comprehensive scaffold database to serve for scaffold-hopping purposes has been created and is publicly available [59]. The database was based on the analysis of more than 4 million compounds to identify 241,824 unique scaffolds. In addition to the scaffold structure, the database contains information about the original molecule and its biological activity as well as its calculated physicochemical properties. 

Another group has evaluated self-organizing maps [63] and shape/ pharmacophore models [64]. They developed a new method termed SQUIRREL to compare molecules in terms of both shape and pharmacophore points. Thus from a commercial library of 199,272 compounds, 1926 were selected based on self-organizing maps trained on peroxisome proliferator-activated receptor a (PPARa) activity islands. The compounds were further evaluated with SQUIRREL and 7 out of 21 molecules selected were found to be active in PPARa. Furthermore, a new virtual screening technique (PhAST) was developed based on representation of molecules as text strings that describe their pharmacophores [65]. 

Finding Bioisosteres in the CSD Scaffold Hopping and Fragment Linking 5.7.1 

FIGURE 15.49 Reversal of functional goups in practolol yields atenolol. 

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Nserum L, Nprskov-Lauritsen L, Olesen PH. Scaffold hopping and optimization towards libraries of glycogen synthase kinase-3 inhibitors. Bioorg Med Chem Lett 2002 12 1525-8. 

Rush, T. S., Grant, J. A., Mosyak, L., Nicholls, A. A shape-based 3-D scaffold hopping method and its application to a bacterial protein-protein interaction. 

Morwick IKKP Potency, physicochem, ADME Pharmacophore model, scaffold hopping [53]... 

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). 

Schneider, G., Neidhart, W., Giller, T., and Schmidt, G. Scaffold-Hopping by topological pharmacophore search a contribution to virtual screening. Angeiv. Chemie. 1999, 111, 3068-3070. 

Ahlstrom, M.M., Ridderstrom, M., Luthman, K. and Zamora, I. (2005) Virtual screening and scaffold hopping based on GRID molecular interaction fields. fournal of Chemical Information and Modeling, 45, 1313-1323. 

Schneider G, Neidhart W, Giller T, Schmid G. (1999) Scaffold-hopping by topological pharmacophore search A contribution to virtual screening. Angew. Chem. Int. Ed. Engl. 38 2894—2896. 

Bohm HJ, Flohr A, Stahl M. (2004) Scaffold hopping. Drug Discov. Today Technol. 1 217-224. 

Enhanced Screening, Scaffold Hopping, Novel Scaffolds... 

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

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