Molecular modeling and design of regioselectively addressable functionalized templates with rigidified three-dimensional structures

Extensive conformational analysis of a series of beta-alkyl substituted cyclopeptides-cyclo(Pro(1)-Xaa(2)-Nle(3)-Ala(4)-Nle(5)-Pro(6) Xaa(7)-Nle(8)-Ala(9)-Nle(10)) and cyclo[Pro(1)-Xaa(2)-Nle(3)-(Cys(4)-Nle(5)-Pro(6)-Xaa(7)-Nle(8)-Cys(9))-N le(10)] as well as their corresponding unsubstituted core structures cyclo(Pro(1)-Xaa(2)-Ala(3)-Cys(4)-Ala(5)-Pro(6)-Xaa(7)-Ala(8)-Ala(9)-Ala (10)) and cyclo(Pro(1)-Xaa(2)-Ala(3)-Cys(4)-Ala(5)-Pro(6)-Xaa(7)-Ala(8)-Cys(9)-Ala (10)) has been performed employing both the ECEPP/2 and the MAB force fields (Xaa = Gly, L-Ala, D-Ala, Aib, and D-Pro). Results show that (a) possible three-dimensional structures of the cyclo(Pro(1)-Gly(2)-Lys(3)-Ala(4)-Lys(5)-Pro(6)-Gly(7)-Lys(8)-Ala(9)-Lys (10)) molecule are nor limited to a single extended "rectangular" conformation with all Lys side chains oriented at the same side of the molecule; (b) conformational equilibrium in monocyclic analogues obtained by replacements of conformationally flexible Gly residues for L-Ala, D-Ala, Aib, or D-Pro is not significantly shifted towards the target "rectangular" conformational type; and (c) introduction of disulfide bridges between positions 4 and 9 is a very powerful way to stabilize the target conformations in the resulting bicyclic molecules. These findings form the basis for further design of rigidified regioselectively addressable functionalized templates with many application areas ranging from biostructural to diagnostic purposes. (C) 1999 John Wiley & Sons, Inc.