Identification of c[D-Trp-Phe-β-Ala-β-Ala], the First κ-Opioid Receptor-Specific Negative Allosteric Modulator.

Recently, the fungus secondary metabolite cyclotetrapetide c[Trp-Phe-D-Pro-Phe] (CJ-15,208) and its derivatives deserved some attention for their unusual structure and distinctive in vitro and in vivo activity. These tryptophan-containing noncationic opioid peptides can be truly regarded as versatile picklocks capable of activating all opioid receptors. Intriguingly, minimal modification of the potent κ-opioid receptor (KOR) agonist c[D-Trp-Phe-Gly-β-Ala] () yielded c[D-Trp-Phe-β-Ala-β-Ala] (), the first KOR-specific negative allosteric modulator (NAM) reported to-date.

Peptidomimetic inhibitors of the VEGF-A/NRP-1 complex obtained by modification of the C-terminal arginine.

Inhibitors of the interaction between Neuropilin-1 (NRP-1) and Vascular Endothelial Growth Factor-A (VEGF-A) hold significant promise as therapeutic and diagnostic agents directed against cancers overexpressing NRP-1. In our efforts in this field, a few series of strong and fairly stable peptide-like inhibitors of the general formula Lys(Har)-Xaa-Xaa-Arg have been previously discovered. In the current work, we focused on Lys(Har)-Dap/Dab-Pro-Arg sequence.

Can We Go beyond Pathology? The Prognostic Role of Risk Scoring Tools for Cancer-Specific Survival of Patients with Bladder Cancer Undergoing Radical Cystectomy.

Radical cystectomy (RC) remains a mainstay surgical treatment for non-metastatic muscle-invasive and BCG-unresponsive bladder cancer. Various perioperative scoring tools assess comorbidity burden, complication risks, and cancer-specific mortality (CSM) risk. We investigated the prognostic value of these scores in patients who underwent RC between 2015 and 2021.

Applications of biaryl cyclization in the synthesis of cyclic enkephalin analogs with a highly restricted flexibility.

A series of 10 cyclic, biaryl analogs of enkephalin, with Tyr or Phe residues at positions 1 and 4, were synthesized according to the Miyaura borylation and Suzuki coupling methodology. Biaryl bridges formed by side chains of the two aromatic amino acid residues are of the meta-meta, meta-para, para-meta, and para-para configuration. Conformational properties of the peptides were studied by CD and NMR.

Synthesis And Anticancer Activity Of New Hybrid 3-Methylidene-2,3-Dihydro-1,8-Naphthyridinones.

Synthesis of molecular hybrids, obtained by combination of two or more pharmacophoric groups of different bioactive substances in order to produce more efficient drugs, is now a frequently used approach in medicinal chemistry. Following this strategy, we synthetized a library of 3-methylidene-1-tosyl-2,3-dihydro-1,8-naphthyridin-4(1H)-ones, combining a 1,8-naphthyridin-4-one motif with an exo-methylidene bond conjugated with a carbonyl group, pharmacophoric units that are present in many natural, biologically active compounds with anticancer potential. We reasoned that such bifunctional conjugates may have enhanced cytotoxic activity.

Moving out of CF -Land: Synthesis, Receptor Affinity, and in silico Studies of NK1 Receptor Ligands Containing a Pentafluorosulfanyl (SF ) Group.

The NK1 receptor (NK1R) is a molecular target for both approved and experimental drugs intended for a variety of conditions, including emesis, pain, and cancers. While contemplating modifications to the typical NK1R pharmacophore, we wondered whether the CF groups common for many NK1R ligands, could be replaced with some other moiety. Our attention was drawn by the SF group, and so we designed, synthesized, and tested ten novel SF -containing compounds for NK1R affinity.

The influence of a synthetic growth hormone-releasing hormone analogue G11 and opioid peptide biphalin on selected fibroblasts parameters relevant to wound healing.

The treatment of hard-to-heal chronic wounds is still a major medical problem and an economic and social burden. In this work, we examine the proregenerative potential of two peptides, G11 (a trypsin-resistant analogue of growth hormone-releasing hormone [GHRH]) and biphalin (opioid peptide), and their combination in vitro on human fibroblasts (BJ). G11, biphalin and their combination exhibited no toxicity against BJ cells.

Gα-derived peptide binds the µ-opioid receptor.

Background: G protein-coupled receptors (GPCRs) transduce external stimuli into the cell by G proteins via an allosteric mechanism. Agonist binding to the receptor stimulates GDP/GTP exchange within the heterotrimeric G protein complex, whereas recent structures of GPCR-G protein complexes revealed that the H5, S1 and S2 domains of Gα are involved in binding the active receptor, earlier studies showed that a short peptide analog derived from the C-terminus (H5) of the G protein transducin (G) is sufficient to stabilize rhodopsin in an active form.

Methods: We have used Molecular Dynamics simulations along with biological evaluation by means of radio-ligand binding assay to study the interactions between Gα-derived peptide (G-peptide) and the µ-opioid receptor (µOR).

Docking is not enough: 17-trifluoromethylphenyl trinor PGF2α is only a very weak ligand of neurokinin-1 receptor.

17-trifluoromethylphenyl trinor prostaglandin F (17-CFPTPGF) was reported recently to exhibit in vitro and in vivo anticancer activity. Based solely on the results of in silico molecular docking, it was claimed that this compound is NK1 receptor (NK1R) antagonist and that its activity is through this receptor. In this contribution we show that 17-CFPTPGF is only a very weak NK1R ligand (IC > 200 μM).

Improving short-term water demand forecasting using evolutionary algorithms.

Modern solutions in water distribution systems are based on monitoring the quality and quantity of drinking water. Identifying the volume of water consumption is the main element of the tools embedded in water demand forecasting (WDF) systems. The crucial element in forecasting is the influence of random factors on the identification of water consumption, which includes, among others, weather conditions and anthropogenic aspects.

In Vitro Biological Evaluation of Aprepitant Based Lu-Radioconjugates.

Currently, the search for promising NK1R-positive tumor-targeting radiopharmaceuticals based on the structure of small molecular antagonists of neurokinin-1 receptor can be observed. Following this trend, we continued our evaluation of aprepitant-based Lu-radioconjugates in terms of future oncological applications. For this purpose, three novel aprepitant homologues were synthesized to broaden the previously obtained derivative portfolio, functionalized with the DOTA chelator and labeled with Ga and Lu.

Fentanyl Structure as a Scaffold for Opioid/Non-Opioid Multitarget Analgesics.

One of the strategies in the search for safe and effective analgesic drugs is the design of multitarget analgesics. Such compounds are intended to have high affinity and activity at more than one molecular target involved in pain modulation. In the present contribution we summarize the attempts in which fentanyl or its substructures were used as a μ-opioid receptor pharmacophoric fragment and a scaffold to which fragments related to non-opioid receptors were attached.

Novel NK1R-Targeted Ga-/Lu-Radioconjugates with Potential Application against Glioblastoma Multiforme: Preliminary Exploration of Structure-Activity Relationships.

Locoregionally administered, NK1 receptor (NK1R) targeted radionuclide therapy is a promising strategy for the treatment of glioblastoma multiforme. So far, the radiopharmaceuticals used in this approach have been based on the endogenous agonist of NK1R, Substance P or on its close analogues. Herein, we used a well-known, small molecular NK1R antagonist, L732,138, as the basis for the radiopharmaceutical vector.

The View Outside of the Box: Reporting Outcomes Following Radical Cystectomy Using Pentafecta From a Multicenter Retrospective Analysis.

We aimed at characterization of the patients undergoing radical cystectomy (RC) using the prognostic model (a modified pentafecta). In the multicenter retrospective study, we enrolled 304 patients with bladder cancer (pTis-4N0-2M0) who underwent RC between 2015 and 2020 in experienced centers. The definition of the pentafecta was as follows: no Clavien-Dindo grade III-V complications at 90 days and no long-term complications related to urinary diversion <12 months, negative surgical margins, ≥10 lymph nodes (LNs) resected, and no recurrence ≤12 months.

Bifunctional Opioid/Melanocortin Peptidomimetics for Use in Neuropathic Pain: Variation in the Type and Length of the Linker Connecting the Two Pharmacophores.

Based on the mechanism of neuropathic pain induction, a new type of bifunctional hybrid peptidomimetics was obtained for potential use in this type of pain. Hybrids consist of two types of pharmacophores that are connected by different types of linkers. The first pharmacophore is an opioid agonist, and the second pharmacophore is an antagonist of the pronociceptive system, i.

Synthesis, Pharmacological Evaluation, and Computational Studies of Cyclic Opioid Peptidomimetics Containing β-Lysine.

Our formerly described pentapeptide opioid analog Tyr-c[D-Lys-Phe-Phe-Asp]NH (designated ), showing high affinity for the mu (MOR) and kappa (KOR) opioid receptors, was much more stable than endomorphine-2 (EM-2) in the rat brain homogenate and displayed remarkable antinociceptive activity after central (intracerebroventricular) and peripheral (intravenous ) administration. In this report, we describe the further modification of this analog, which includes the incorporation of a β-amino acid, ()- and ()-β-Lys, instead of D-Lys in position 2. The influence of such replacement on the biological properties of the obtained analogs, Tyr-c[()-β-Lys-Phe-Phe-Asp]NH () and Tyr-c[()-β-Lys-Phe-Phe-Asp]NH, (), was investigated in vitro.

The solid state VCD of a novel N-acylhydrazone trifluoroacetate.

A novel N-acylhydrazone with pharmaceutical importance was subject of structural and IR/VCD investigations in the solid state. In the crystal structure, dimers of anion-cation pairs are stabilized by H-bonding and ionic interactions. Some less common interaction types, like C=N···C-NH (σ-hole) interactions, hydrazone-aromatic interactions and dispersive contacts of the CF groups are also present in the crystal.

PSMA-D4 Radioligand for Targeted Therapy of Prostate Cancer: Synthesis, Characteristics and Preliminary Assessment of Biological Properties.

A new PSMA ligand (PSMA-D4) containing the Glu-CO-Lys pharmacophore connected with a new linker system (L-Trp-4-Amc) and chelator DOTA was developed for radiolabeling with therapeutic radionuclides. Herein we describe the synthesis, radiolabeling, and preliminary biological evaluation of the novel PSMA-D4 ligand. Synthesized PSMA-D4 was characterized using TOF-ESI-MS, NMR, and HPLC methods.

Prototype of a Textronic Sensor Created with a Physical Vacuum Deposition Process for Detection.

is a bacterium which people have been in contact with for thousands of years. Its presence often leads to severe disorders of the respiratory and circulatory systems. The authors of this article present a prototype of a textronic sensor enabling the detection of this bacterium.

Real-Time Parallel-Serial LiDAR-Based Localization Algorithm with Centimeter Accuracy for GPS-Denied Environments.

In this paper, we introduce a real-time parallel-serial algorithm for autonomous robot positioning for GPS-denied, dark environments, such as caves and mine galleries. To achieve a good complexity-accuracy trade-off, we fuse data from light detection and ranging (LiDAR) and an inertial measurement unit (IMU). The proposed algorithm's main novelty is that, unlike in most algorithms, we apply an extended Kalman filter (EKF) to each LiDAR scan point and calculate the location relative to a triangular mesh.

Identification of miRNA Biomarkers for Diverse Cancer Types Using Statistical Learning Methods at the Whole-Genome Scale.

Genome-wide analysis of miRNA molecules can reveal important information for understanding the biology of cancer. Typically, miRNAs are used as features in statistical learning methods in order to train learning models to predict cancer. This motivates us to propose a method that integrates clustering and classification techniques for diverse cancer types with survival analysis via regression to identify miRNAs that can potentially play a crucial role in the prediction of different types of tumors.

Decision Tree-Based Classification for Planetary Gearboxes' Condition Monitoring with the Use of Vibration Data in Multidimensional Symptom Space.

Monitoring the condition of rotating machinery, especially planetary gearboxes, is a challenging problem. In most of the available approaches, diagnostic procedures are related to advanced signal pre-processing/feature extraction methods or advanced data (features) analysis by using artificial intelligence. In this paper, the second approach is explored, so an application of decision trees for the classification of spectral-based 15D vectors of diagnostic data is proposed.