Matching organic libraries with protein-substructures

We present a general approach which allows automatic identification of sub-structures in proteins that resemble given three-dimensional templates. This paper documents its success with non-peptide templates such as beta-turn mimetics. We considered well-tested turn-mimetics such as the bicyclic turned dipeptide (BTD), spiro lactam (Spiro) and the 2,5-disubstituded tetrahydrofuran (THF), a new furan-derivative which was recently developed and characterized. The detected geometric similarity between the templates and the protein patches corresponds to r.m.s.-values of 0.3 A for more than 80% of the constituting atoms, which is typical for active site comparisons of homologous proteins. This fast automatic procedure might be of biomedical value for finding special mimicking leads for particular protein sub-structures as well as for template-assembled synthetic protein (TASP) design.