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

Abstract

Targeting the polyamine biosynthetic pathway by inhibiting ornithine decarboxylase (ODC) is a powerful approach in the fight against diverse viruses, including SARS-CoV-2. Difluoromethylornithine (DFMO, eflornithine) is the best-known inhibitor of ODC and a broad-spectrum, unique therapeutical agent. Nevertheless, its pharmacokinetic profile is not perfect, especially when large doses are required in antiviral treatment. This article presents a holistic study focusing on the molecular and supramolecular structure of DFMO and the design of its analogues toward the development of safer and more effective formulations. In this context, we provide the first deep insight into the supramolecular system of DFMO supplemented by a comprehensive, qualitative and quantitative survey of non-covalent interactions via Hirshfeld surface, molecular electrostatic potential, enrichment ratio and energy frameworks analysis visualizing 3-D topology of interactions in order to understand the differences in the cooperativity of interactions involved in the formation of either basic or large synthons (Long-range Synthon Aufbau Modules, LSAM) at the subsequent levels of well-organized supramolecular self-assembly, in comparison with the ornithine structure. In the light of the drug discovery, supramolecular studies of amino acids, essential constituents of proteins, are of prime importance. In brief, the same amino-carboxy synthons are observed in the bio-system containing DFMO. DFT calculations revealed that the biological environment changes the molecular structure of DFMO only slightly. The ADMET profile of structural modifications of DFMO and optimization of its analogue as a new promising drug via molecular docking are discussed in detail.

Chemoenzymatic Synthesis of Optically Active Ethereal Analog of iso-Moramide—A Novel Potentially Powerful Analgesic †

“…Molecular docking calculations were performed with AutoDock Vina v. 1.1.2. program ( , accessed on 5 September 2022) [ 43 ] using the standard docking protocol described in our recent studies [ 65 , 66 ]. All ligands were prepared with ChemAxon MarvinSketch v. 14.9.1.0 ( , accessed on 5 September 2022), optimized in terms of geometry in Avogadro v. 1.2.0.…”

Smart therapies against global pandemics: A potential of short peptides

“…To sum up, short peptides and even simple derived amino acids ( Bojarska et al, 2021 ) have huge potential in the treatment of pandemic-prone pathogens, as a broad-spectrum agents.…”

Supramolecular synthon hierarchy in cyclopropyl-containing peptide-derived compounds

“…Molecular docking calculations were performed with AutoDock Vina vs. 1.1.2. program (http://autodock.scripps.edu/) using the standard docking protocol described in our recent study (for more details, see Supplementary information). 52 All ligands were prepared with ChemAxon MarvinSketch vs. 14.9.1.0 (http://www.chemaxon.com/marvin/), optimized in terms of geometry in Avogadro vs. 1.2.0. (http://avogadro.cc/), and saved as .mol2 files.…”

“…These studies fit into the mainstream of our ongoing project that concentrates on supramolecular exploration and bioactivity of peptide-based molecules. 37,38,44–82…”