A Supramolecular Approach to Structure-Based Design with A Focus on Synthons Hierarchy in Ornithine-Derived Ligands: Review, Synthesis, Experimental and in Silico Studies

Abstract

The success of innovative drugs depends on an interdisciplinary and holistic approach to their design and development. The supramolecular architecture of living systems is controlled by non-covalent interactions to a very large extent. The latter are prone to extensive cooperation and like a virtuoso play a symphony of life. Thus, the design of effective ligands should be based on thorough knowledge on the interactions at either a molecular or high topological level. In this work, we emphasize the importance of supramolecular structure and ligand-based design keeping the potential of supramolecular H-bonding synthons in focus. In this respect, the relevance of supramolecular chemistry for advanced therapies is appreciated and undisputable. It has developed tools, such as Hirshfeld surface analysis, using a huge data on supramolecular interactions in over one million structures which are deposited in the Cambridge Structure Database (CSD). In particular, molecular interaction surfaces are useful for identification of macromolecular active sites followed by in silico docking experiments. Ornithine-derived compounds are a new, promising class of multi-targeting ligands for innovative therapeutics and cosmeceuticals. In this work, we present the synthesis together with the molecular and supramolecular structure of a novel ornithine derivative, namely N-α,N-δ)-dibenzoyl-(α)-hydroxymethylornithine, 1. It was investigated by modern experimental and in silico methods in detail. The incorporation of an aromatic system into the ornithine core induces stacking interactions, which are vital in biological processes. In particular, rare C=O…π intercontacts have been identified in 1. Supramolecular interactions were analyzed in all structures of ornithine derivatives deposited in the CSD. The influence of substituent was assessed by the Hirshfeld surface analysis. It revealed that the crystal packing is stabilized mainly by H…O, O…H, C…H, Cl (Br, F)…H and O…O interactions. Additionally, π…π, C-H…π and N-O…π interactions were also observed. All relevant H-bond energies were calculated using the Lippincott and Schroeder H-bond model. A library of synthons is provided. In addition, the large synthons (Long-Range Synthon Aufbau Module) were considered. The DFT optimization either in vacuo or in solutio yields very similar molecular species. The major difference with the relevant crystal structure was related to the conformation of terminal benzoyl C15-C20 ring. Furthermore, in silico prediction of the extensive physicochemical ADME profile (absorption, distribution, metabolism and excretion) related to the drug-likeness and medicinal chemistry friendliness revealed that a novel ornithine derivative 1 has the potential to be a new drug candidate. It has shown good in silico absorption and very low toxicity.

A Global Review on Short Peptides: Frontiers and Perspectives

“…Supramolecular chemistry (‘‘chemistry beyond the molecule’’) is a bottom-up approach to the formation of well-ordered structures in the nano- (and the micro-) scale. Their adaptable, controllable, self-healing, and bio-physico-chemical stimuli-responsive properties induced via non-covalent interactions (electrostatic, hydrogen bonding, π–π stacking, van der Waals or hydrophobic) are highly appreciated [ 123 , 127 , 128 , 129 , 130 , 131 , 132 ]. They have the dynamic nature and provide a firm basis for the structure and functioning of living systems.…”

“…Modified peptides with aromatic amino acids or functionalized side chains (e.g., Fmoc) promote additional stacking interactions ( Figure 4 ), which are helpful in the self-assembly process. Peptide-based bio-functional supramolecular materials (nanomedicines, hydrogels, drug delivery vehicles, gene or drug carriers, biomimetic-cell culture scaffolds, tissue-engineering systems, biosensors, emulsifiers, peptidomimetic antibiotics, bioimaging nanoprobes, three-dimensional (3D) bioprinting inks, vaccine adjuvants) have low toxicity and high biocompatibility and are useful in various applications, like drug delivery, tissue engineering, immunology, cancer therapy, and stem cell culture [ 38 , 95 , 101 , 131 , 132 , 133 , 134 , 135 , 136 ]. Supramolecular nanotherapeutics have better stability and efficacy, which helps to overcome problems related to peptide poor biostability and short plasma half-life.…”

The First Insight Into the Supramolecular System of D,L-α-Difluoromethylornithine: A New Antiviral Perspective

“…This work is a continuation of our studies focusing on the paramount goal of supramolecular exploration of biologically active systems, especially short peptides and modified amino acids ( Główka, et al, 2004 ; Główka, et al, 2005 ; Główka, et al, 2007 ; Olczak, et al, 2007 ; Olczak, et al, 2010 ; Remko, et al, 2011 ; Bojarska et al, 2012a ; Bojarska et al, 2012b ; Remko et al, 2013 ; Bojarska et al, 2013a ; Bojarska et al, 2013b ; Bojarska et al, 2013c ; Bojarska et al, 2014 ; Bojarska et al, 2015 ; Bojarska and Maniukiewicz, 2015 ; Remko et al, 2015 ; Bojarska et al, 2016 ; Bojarska et al, 2018a ; Bojarska et al, 2018b ; Bojarska et al, 2019a ; Bojarska et al, 2019b ; Bojarska et al, 2019c ; Bojarska et al, 2019d ; Bojarska et al, 2019e ; Bojarska et al, 2020a ; Bojarska et al, 2020b ; Bojarska et al, 2020c ; Bojarska et al, 2020d ). The article is the first one, according to our knowledge, to gain deep supramolecular insight into the very popular drug DFMO ( 1 ) ( Supplementary Figure S1 ), an ornithine derivative ( Bojarska et al, 2020b ), which is still being developed as a promising broad-spectrum therapeutic agent. It is surprising that its crystal structure has not been determined so far, although the compound has been known for almost half a century.…”

“…The flat regions of the HS have low values of curvedness, while the sharp areashigh values of curvedness, leading to the division of the surface into color patches reflecting inter-contacts among the nearest neighboring molecules.The molecular electrostatic potential (ESP) offers a deeper direct insight into the supramolecular interactions within the crystal(Spackman et al, 2008). The title compound 1 has a dipolar nature, similar to ornithine 2(Bojarska et al, 2020b), with clearly separated negative (red area) and positive (blue region) electrostatic potentials, representing H-bond acceptor and donor sites, respectively. The electrostatic complementarity of 1 mapped on its HS is demonstrated inFigure 4.…”

Structure-Based Design of Biologically Active Compounds

“…Based on the concept that the knowledge of interactions at either a molecular or high topological level are important for the design of effective ligands, Bojarska et al [ 9 ] designed and synthesized a novel ornithine derivative and analyzed the molecular and supramolecular structure.…”