Abstract
Proline is a unique, endogenous amino acid, prevalent in proteins and essential for living organisms. It is appreciated as a tecton for the rational design of new bio-active substances. Herein, we present a short overview of the subject. We analyzed 2366 proline-derived structures deposited in the Cambridge Structure Database, with emphasis on the angiotensin-converting enzyme inhibitors. The latter are the first-line antihypertensive and cardiological drugs. Their side effects prompt a search for improved pharmaceuticals. Characterization of tectons (molecular building blocks) and the resulting supramolecular synthons (patterns of intermolecular interactions) involving proline derivatives, as presented in this study, may be useful for in silico molecular docking and macromolecular modeling studies. The DFT, Hirshfeld surface and energy framework methods gave considerable insight into the nature of close inter-contacts and supramolecular topology. Substituents of proline entity are important for the formation and cooperation of synthons. Tectonic subunits contain proline moieties characterized by diverse ionization states: -N and -COOH(-COO−), -N+ and -COOH(-COO−), -NH and -COOH(-COO−), -NH+ and -COOH(-COO−), and -NH2+ and -COOH(-COO−). Furthermore, pharmacological profiles of ACE inhibitors and their impurities were determined via an in silico approach. The above data were used to develop comprehensive classification, which may be useful in further drug design studies.
Highlights
Proline was isolated for the first time by Richard Willstätter in 1900 [1], but its name was coined by Emil Fisher [2] who derived it from its pyrrolidine ring
Twenty proline-based ACEI were subjected to detailed DFT, Hirshfield surface and energy framework studies for the comprehensive description of tectons and synthons
Tectons with NH2+ and COO− and -N and COOH(COO−) functionalities are the most popular. They are observed in the ACEI structures, in which they facilitate the formation of single and bifurcated O–H . . . O, O–H . . . N, N–H . . . O, C–H . . . O, S–H . . . O, and O–H . . . Cl− supramolecular synthons
Summary
Proline was isolated for the first time by Richard Willstätter in 1900 [1], but its name was coined by Emil Fisher [2] who derived it from its pyrrolidine ring. Proline is an untypical and multifunctional endogenous amino acid which is a key constituent of almost all proteins Nowadays, it is gaining relevance in diverse medical applications and drug design studies. Proline adopts two distinct conformations governed by the cis–trans amide bond isomerism and extended by the exo/endo ring puckers. Both cis and trans isomers are almost energetically equivalent [5]. The pyrrolidine ring usually exists in half-chair or envelope conformations [8] They may be conveniently described by two pseudo-rotation parameters, as defined by Altona and Sundaralingam, or the exo/endo puckers [9]. Peptide bonds involving proline residue may adopt either a trans or cis arrangement, which further affects ring conformations. It is worth noting that substitutions on the pyrrolidine ring affect additional steric and stereochemical effects modulating the cis/trans and endo/exo states [16]
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