A Computational Study of Conformational Properties for N-Methylated Azapeptide Models

Abstract

The modification of peptide structures is a general strategy in drug design to increase the resistance to physiological degradation and decrease the conformational flexibility. Among these modifications, azaamino acids are promising peptidomimetic compounds, which are formed by the replacement of an α-carbon of amino acids with a nitrogen atom. Azaamino acids also could be prepared relatively easily with retention of the side chain in the normal amino acid. Recently, our laboratories reported torsion angle based design, solid phase synthesis and conformational study of a β-I turn adopting peptidomimetic template [1]. During these studies, we found that besides Na, two other nitrogens of an azaamino acid can be alkylated. To understand the effects of such alkylation on the conformation of azaamino acid is critical for the design of conformation directed combinatorial libraries. Thus, we carried out computational studies of model azapeptides in which methyl groups are systematically incorporated, Ac-Sar-NHMe (1), Ac-(NMe)AzAla-NHMe (2), Ac-Sar-NMe2(3) and Ac-(NMe)AzAla-NMe2(4).