Exploring Ramachandran and Chi Space: Conformationally Constrained Amino Acids and Peptides in the Design of Bioactive Polypeptide Ligands

Abstract

Ligand binding and concomitant changes in receptor structure provide the means to target signal transduction pathways. With appropriate refinement of the ligand's interaction with the "receptor," one in theory could produce ligands that have greater therapeutic benefits. This review will discuss how, when these ligands are amino acids and peptides, the introduction of appropriate conformational constraints provides a powerful strategy for improved drug design. This review will discuss how various constraints on amino acids can provide a powerful tool for ligand design, determination of the three dimensional pharmacophore and new insights into receptor systems and information transduction. Through the use of constrained ligands, new information regarding their interaction with their "receptor" systems, and further refinement of the use of constraints, scientists can produce more beneficial drugs for mankind.

Peptidomimetics, a synthetic tool of drug discovery

“…The design process begins by developing structure-activity relationships (SAR) that can define a minimal active sequence or major pharmacophore elements, and identify the key residues that are responsible for the biological effect. Then structural constraints are applied to probe the 3-D arrangement(s) of these features [1][2][3][4]. In this process, the peptide complexity is reduced and the basic pharmacophore model is defined by its critical structural features in 3D space.…”

(R)-α-Aminoadipic acid: an interesting chiral pool building block

“…Chemical shifts are reported in ppm and coupling constants in Hertz. 13 C NMR spectra were recorded on the same instrument (125.7 MHz) with total proton decoupling. EI and CI mass spectra (including EI accurate mass measurements) were recorded using an Autospec X magnetic sector mass spectrometer with EBE geometry (Vacuum Generators, Manchester, UK) equipped with a standard EI or CI source.…”

“…Like proline, pipecolic acid is also a valuable building block for the synthesis of conformationally constrained peptides. 13 Hence, a convenient access to (R)-pipecolic acid is of importance because it is a key constituent of bioactive molecules, a useful building block for asymmetric synthesis and a versatile organocatalyst.…”

Synthesis of new functionalized aziridine-2- and azetidine-3-carboxylic acid derivatives of potential interest for biological and foldameric applications

“…In view of the importance of the aforementioned classes of amino acids, the development of pathways to new three-and four-membered azaheterocyclic α-and β-amino acid derivatives is a challenging research field in modern synthetic chemistry at the biological interface (Hughes 2009a;Kiss and Fülöp 2010;Fülöp et al 2006;Kuhl et al 2005;Miller and Nguyen 2005;Cativiela and Ordóñez 2009;Komarov et al 2004;Cowell et al 2004;Gelmi and Pocar 2003;Park and Kurth 2002). Following a preliminary communication (Mangelinckx et al 2008), in the present paper, in-depth results are described on the synthesis and study of the reactivity of 2-(bromomethyl)aziridine-2-carboxylic esters and 3-bromoazetidine-3-carboxylic esters, the structures of which incorporate the synthetically important 2-(halomethyl)aziridine (Abbaspour Tehrani et al 2002;De Smaele et al 1998;De Kimpe et al 1997;D'hooghe et al 2006a;Mangelinckx et al 2009;Vervisch et al 2010), or 3-haloazetidine structural motif (Van Driessche et al 2006;Van Brabandt et al 2009).…”