Peptides are fragments of proteins that carry out biological functions. They act as signaling entities via all domains of life and interfere with protein-protein interactions, which are indispensable ...in bio-processes. Short peptides include fundamental molecular information for a prelude to the symphony of life. They have aroused considerable interest due to their unique features and great promise in innovative bio-therapies. This work focusing on the current state-of-the-art short peptide-based therapeutical developments is the first global review written by researchers from all continents, as a celebration of 100 years of peptide therapeutics since the commencement of insulin therapy in the 1920s. Peptide "drugs" initially played only the role of hormone analogs to balance disorders. Nowadays, they achieve numerous biomedical tasks, can cross membranes, or reach intracellular targets. The role of peptides in bio-processes can hardly be mimicked by other chemical substances. The article is divided into independent sections, which are related to either the progress in short peptide-based theranostics or the problems posing challenge to bio-medicine. In particular, the SWOT analysis of short peptides, their relevance in therapies of diverse diseases, improvements in (bio)synthesis platforms, advanced nano-supramolecular technologies, aptamers, altered peptide ligands and in silico methodologies to overcome peptide limitations, modern smart bio-functional materials, vaccines, and drug/gene-targeted delivery systems are discussed.
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
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
-α,
-δ)-dibenzoyl-(α)-hydroxymethylornithine,
. It was investigated by modern experimental and
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
. 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 (
) were considered. The DFT optimization either
or
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,
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
has the potential to be a new drug candidate. It has shown good
absorption and very low toxicity.
Interactions between metal ions and amino acids are common both in solution and in the gas phase. Here, the effect of metal ions and water on the structure of glycine is examined. The effect of metal ...ions (Li+, Na+, K+, Mg2+, Ca2+, Ni2+, Cu2+, and Zn2+) and water on structures of Gly·M n +(H2O) m and GlyZwitt·M n +(H2O) m (m = 0, 2, 5) complexes have been determined theoretically by employing the hybrid B3LYP exchange-correlation functional and using extended basis sets. Selected calculations were carried out also by means of CBS-QB3 model chemistry. The interaction enthalpies, entropies, and Gibbs energies of eight complexes Gly·M n + (M n + = Li+, Na+, K+, Mg2+, Ca2+, Ni2+, Cu2+, and Zn2+) were determined at the B3LYP density functional level of theory. The computed Gibbs energies ΔG° are negative and span a rather broad energy interval (from −90 to −1100 kJ mol-1), meaning that the ions studied form strong complexes. The largest interaction Gibbs energy (−1076 kJ mol-1) was computed for the NiGly2+ complex. Calculations of the molecular structure and relative stability of the Gly·M n +(H2O) m and GlyZwitt·M n +(H2O) m (M n + = Li+, Na+, K+, Mg2+, Ca2+, Ni2+, Cu2+, and Zn2+; m = 0, 2, and 5) systems indicate that in the complexes with monovalent metal cations the most stable species are the NO coordinated metal cations in non-zwitterionic glycine. Divalent cations Mg2+, Ca2+, Ni2+, Cu2+, and Zn2+ prefer coordination via the OO bifurcated bonds of the zwitterionic glycine. Stepwise addition of two and five water molecules leads to considerable changes in the relative stability of the hydrated species. Addition of two water molecules at the metal ion in both Gly·M n + and GlyZwitt·M n + complexes reduces the relative stability of metallic complexes of glycine. For M n + = Li+ or Na+, the addition of five water molecules does not change the relative order of stability. In the Gly·K+ complex, the solvation shell of water molecules around K+ ion has, because of the larger size of the potassium cation, a different structure with a reduced number of hydrogen-bonded contacts. This results in a net preference (by 10.3 kJ mol-1) of the GlyZwitt·K+(H2O)5 system. Addition of five water molecules to the glycine complexes containing divalent cations Mg2+, Ca2+, Ni2+, Cu2+, and Zn2+ results in a net preference for non-zwitterionic glycine species. The computed relative Gibbs energies are quite high (−10 to −38 kJ mol-1), and the NO coordination is preferred in the Gly·M n +(H2O)5 (M n + = Mg2+, Ca2+, Ni2+, Cu2+, and Zn2+) complexes over the OO coordination.
Theoretical chemistry methods have been used to study the molecular properties of antiplatelet agents (ticlopidine, clopidogrel, prasugrel, elinogrel, ticagrelor and cangrelor) and several ...thiol-containing active metabolites. The geometries and energies of most stable conformers of these drugs have been computed at the Becke3LYP/6-311++G(d,p) level of density functional theory. Computed dissociation constants show that the active metabolites of prodrugs (ticlopidine, clopidogrel and prasugrel) and drugs elinogrel and cangrelor are completely ionized at pH 7.4. Both ticagrelor and its active metabolite are present at pH = 7.4 in neutral undissociated form. The thienopyridine prodrugs ticlopidine, clopidogrel and prasugrel are lipophilic and insoluble in water. Their lipophilicity is very high (about 2.5-3.5 logP values). The polar surface area, with regard to the structurally-heterogeneous character of these antiplatelet drugs, is from very large interval of values of 3-255 Ų. Thienopyridine prodrugs, like ticlopidine, clopidogrel and prasugrel, with the lowest polar surface area (PSA) values, exhibit the largest absorption. A high value of polar surface area (PSA) of cangrelor (255 Ų) results in substantial worsening of the absorption in comparison with thienopyridine drugs.
The geometries and energies of factor Xa inhibitors edoxaban, eribaxaban, fidexaban, darexaban, letaxaban, and the dual factor Xa and thrombin inhibitors tanogitran and SAR107375 in both the ...gas-phase and aqueous solution were studied using the Becke3LYP/6-31++G(d,p) or Grimme's B97D/6-31++G(d,p) method. The fully optimized conformers of these anticoagulants show a characteristic l-shape structure, and the water had a remarkable effect on the equilibrium geometry. According to the calculated pKa values eribaxaban and letaxaban are in neutral undissociated form at pH 7.4, while fidexaban and tanogitran exist as zwitterionic structures. The lipophilicity of the inhibitors studied lies within a large range of log P between 1 and 4. The dual inhibitor SAR107375 represents an improvement in structural, physicochemical and pharmacokinetic characteristics over tanogitran. At blood pH, SAR107375 predominantly exists in neutral form. In contrast with tanogitran, it is better absorbed and more lipophilic and active after oral application.
Interactions between metal ions and amino acids are common both in solution and in the gas phase. The effect of metal ions and water on the structure of l-histidine is examined. The effect of metal ...ions (Li⁺, Na⁺, K⁺, Mg²⁺, Ca²⁺, Ni²⁺, Cu²⁺ and Zn²⁺) and water on structures of His·M(H₂O)m, m = 0.1 complexes have been determined theoretically employing density functional theories using extended basis sets. Of the five stable complexes investigated the relative stability of the gas-phase complexes computed with DFT methods (with one exception of K⁺ systems) suggest metallic complexes of the neutral l-histidine to be the most stable species. The calculations of monohydrated systems show that even one water molecule has a profound effect on the relative stability of individual complexes. Proton dissociation enthalpies and Gibbs energies of l-histidine in the presence of the metal cations Li⁺, Na⁺, K⁺, Mg²⁺, Ca²⁺, Ni²⁺, Cu²⁺ and Zn²⁺ were also computed. Its gas-phase acidity considerably increases upon chelation. Of the Lewis acids investigated, the strongest affinity to l-histidine is exhibited by the Cu²⁺ cation. The computed Gibbs energies ΔG are negative, span a rather broad energy interval (from −130 to −1,300 kJ/mol), and upon hydration are appreciably lowered.
Density functional theory methods with the B3LYP functional have been used to study the acidity of carboxylate, O-sulfate and N-sulfate groups in six basic monomeric structural units of heparin ...(1-OMe ΔUA-2S, 1-OMe GlcN-S6S, 1,4-DiOMe GlcA, 1,4-DiOMe GlcN-S3S6S, 1,4-DiOMe IdoA-2S, and 1,4-DiOMe GlcN-S6S).
•Acidity of monomeric structural units of heparin.•The monomers are in gas-phase weak organic acids.•The ionization of the second acidic group occurs less readily than the first.•The acidity order of acidic functional groups is: O-sulfo>N-sulfo>carboxyl.•The same order of acidity was observed also in water solution.
Density functional theory methods with the B3LYP functional have been used to letter the acidity of carboxyl, O-sulfo and N-sulfo groups in six basic monomeric structural units of heparin (1-OMe ΔUA-2S, 1-OMe GlcN-S6S, 1,4-DiOMe GlcA, 1,4-DiOMe GlcN-S3S6S, 1,4-DiOMe IdoA-2S, and 1,4-DiOMe GlcN-S6S). The predicted gas-phase acidity of the acidic functional groups in the monomeric structural units of heparin is: O-sulfo>N-sulfo>carboxyl. The computed pKa values provide the same order of acidity as was observed in water solution. This implies that hydration does not change ordering of acidity of major acidic groups of monomeric structural units of heparin.
Short peptides have great potential as safe and effective anticancer drug leads. Herein, the influence of short cyclic peptides containing the Pro-Pro-Phe-Phe sequence on patient-derived melanoma ...cells was investigated. Cyclic peptides such as cyclo(Leu-Ile-Ile-Leu-Val-Pro-Pro-Phe-Phe-), called CLA, and cyclo(Pro-homoPro-β3homoPhe-Phe-), called P11, exert the cytotoxic and the cytostatic effects in melanoma cells, respectively. CLA was the most active peptide as it reduced the viability of melanoma cells to 50% of control at about 10 µM, whereas P11 at about 40 µM after 48 h incubation. Interestingly, a linear derivative of P11 did not induce any effect in melanoma cells confirming previous studies showing that cyclic peptides exert better biological activity compared to their linear counterparts. According to in silico predictions, cyclic tetrapeptides show a better pharmacokinetic and toxic profile to humans than CLA. Notably, the spatial structure of those peptides containing synthetic amino acids has not been explored yet. In the Cambridge Structural Database, there is only one such cyclic tetrapeptide, cyclo((R)-β2homoPhe-D-Pro-Lys-Phe-), while in the Protein Data Bank—none. Therefore, we report the first crystal structure of cyclo(Pro-Pro-β3homoPhe-Phe-), denoted as 4B8M, a close analog of P11, which is crucial for drug discovery. Comparative molecular and supramolecular analysis of both structures was performed. The DFT findings revealed that 4B8M is well interpreted in the water solution. The results of complex Hirshfeld surface investigations on the cooperativity of interatomic contacts in terms of electrostatic and energetic features are provided. In short, the enrichment ratio revealed O…H/H…O and C…H/H…C as privileged intercontacts in the crystals in relation to basic and large supramolecular H-bonding synthon patterns. Furthermore, the ability of self-assemble 4B8M leading to a nanotubular structure is also discussed.
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 -NH
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.
Interactions between metal ions and amino acids are common both in solution and in the gas phase. The effect of metal ions and water on the structure of l-arginine is examined. The effects of metal ...ions (Li+, Na+, K+, Mg2+, Ca2+, Ni2+, Cu2+, and Zn2+) and water on structures of Arg•M(H2O) m , m = 0, 1 complexes have been determined theoretically by employing the density functional theories (DFT) and using extended basis sets. Of the three stable complexes investigated, the relative stability of the gas-phase complexes computed with DFT methods (with the exception of K+ systems) suggests metallic complexes of the neutral l-arginine to be the most stable species. The calculations of monohydrated systems show that even one water molecule has a profound effect on the relative stability of individual complexes. Proton dissociation enthalpies and Gibbs energies of arginine in the presence of the metal cations Li+, Na+, K+, Mg2+, Ca2+, Ni2+, Cu2+, and Zn2+ were also computed. Its gas-phase acidity considerably increases upon chelation. Of the Lewis acids investigated, the strongest affinity to arginine is exhibited by the Cu2+ cation. The computed Gibbs energies ΔG o are negative, span a rather broad energy interval (from −150 to −1500 kJ/mol), and are appreciably lowered upon hydration.
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