GraphCPP: The new state-of-the-art method for cell-penetrating peptide prediction via graph neural networks.

Background And Purpose: Cell-penetrating peptides (CPPs) are short amino acid sequences that can penetrate cell membranes and deliver molecules into cells. Several models have been developed for their discovery, yet these models often face challenges in accurately predicting membrane penetration due to the complex nature of peptide-cell interactions. Hence, there is a need for innovative approaches that can enhance predictive performance.

Sustainable and Safe -alkylation of -heterocycles by Propylene Carbonate under Neat Reaction Conditions.

A new, eco-friendly process utilising the green solvent propylene carbonate (PC) has been developed to perform -alkylation of -, - and/or -containing heterocyclic compounds. PC in these reactions served as both the reagent and solvent. Importantly, no genotoxic alkyl halides were required.

Advantages of Induced Circular Dichroism Spectroscopy for Qualitative and Quantitative Analysis of Solution-Phase Cyclodextrin Host-Guest Complexes.

The presence of a chiral or chirally perturbed chromophore in the molecule under investigation is a fundamental requirement for the appearance of a circular dichroism (CD) spectrum. For native and for most of the substituted cyclodextrins, this condition is not applicable, because although chiral, cyclodextrins lack a chromophore group and therefore have no characteristic CD spectra over 220 nm. The reason this method can be used is that if the guest molecule has a chromophore group and this is in the right proximity to the cyclodextrin, it becomes chirally perturbed.

Molecular Dynamics Simulations of Drug-Conjugated Cell-Penetrating Peptides.

Cell-penetrating peptides (CPPs) are small peptides capable of translocating through biological membranes carrying various attached cargo into cells and even into the nucleus. They may also participate in transcellular transport. Our in silico study intends to model several peptides and their conjugates.

Small Molecules as Toll-like Receptor 4 Modulators Drug and Computational Repurposing.

The innate immunity toll-like receptor 4 (TLR4) system is a receptor of paramount importance as a therapeutic target. Virtual screening following a "computer-aided drug repurposing" approach was applied to the discovery of novel TLR4 modulators with a non-lipopolysaccharide-like structure. We screened almost 29,000 approved drugs and drug-like molecules from commercial, public, and academia chemical libraries and, after biological assays, identified several compounds with TLR4 antagonist activity.

ConjuPepDB: a database of peptide-drug conjugates.

Peptide-drug conjugates are organic molecules composed of (i) a small drug molecule, (ii) a peptide and (iii) a linker. The drug molecule is mandatory for the biological action, however, its efficacy can be enhanced by targeted delivery, which often also reduces unwanted side effects. For site-specificity the peptide part is mainly responsible.

Design and Selection of Novel C1s Inhibitors by In Silico and In Vitro Approaches.

The complement system is associated with various diseases such as inflammation or auto-immune diseases. Complement-targeted drugs could provide novel therapeutic intervention against the above diseases. C1s, a serine protease, plays an important role in the CS and could be an attractive target since it blocks the system at an early stage of the complement cascade.

Investigation of Isoindolo[2,1-a]quinoxaline-6-imines as Topoisomerase I Inhibitors with Molecular Modeling Methods.

Background: Isoindolo[2,1-a]quinoxalines constitute an important class of compounds which demonstrated potent antiproliferative activity against different human tumor cell lines and topoisomerase I inhibitors. In particular, their water soluble imine or iminium salts recently synthesized showed potent growth inhibitory effect on NCI-60 tumor cell line panel and biological studies performed on the most active compounds demonstrated that they cause DNA damage via topoisomerase I poisoning.

Objective: Herein, we investigate with molecular modeling methods, the common features responsible for topoisomerase I inhibition of the water-soluble isoindolo[2,1-a]quinoxalin-6-imines, by comparing them with known inhibitors.

Piceatannol and resveratrol share inhibitory effects on hydrogen peroxide release, monoamine oxidase and lipogenic activities in adipose tissue, but differ in their antilipolytic properties.

Piceatannol is a hydroxylated derivative of resveratrol. While both dietary polyphenols coexist in edible plants and fruits, and share equivalent concentrations in several wines, the influence of piceatannol on adiposity has been less studied than that of resveratrol. Though resveratrol is now recognized to limit fat deposition in various obesity models, the benefit of its dietary supplementation remains under debate regarding human obesity treatment or prevention.

Dietary Phenolic Compounds Interfere with the Fate of Hydrogen Peroxide in Human Adipose Tissue but Do Not Directly Inhibit Primary Amine Oxidase Activity.

Resveratrol has been reported to inhibit monoamine oxidases (MAO). Many substrates or inhibitors of neuronal MAO interact also with other amine oxidases (AO) in peripheral organs, such as semicarbazide-sensitive AO (SSAO), known as primary amine oxidase, absent in neurones, but abundant in adipocytes. We asked whether phenolic compounds (resveratrol, pterostilbene, quercetin, and caffeic acid) behave as MAO and SSAO inhibitors.

Water-soluble isoindolo[2,1-a]quinoxalin-6-imines: in vitro antiproliferative activity and molecular mechanism(s) of action.

Water-soluble isoindoloquinoxalin (IIQ) imines and the corresponding acetates were conveniently prepared from the key intermediates 2-(2'-aminophenyl)-2H-isoindole-1-carbonitriles obtained by a Strecker reaction between substituted 1,2-dicarbaldehydes and 1,2-phenylenediamines. Both series were screened by the National Cancer Institute (Bethesda, MD) and showed potent antiproliferative activity against a panel of 60 human tumor cell lines. Several of the novel compounds showed GI50 values at a nanomolar level on the majority of the tested cell lines.

Analysis of Edg-Like LPA Receptor-Ligand Interactions.

The phospholipid derivative lysophosphatidic acid (LPA) serves as a signalling molecule through the activation of LPA receptors, which belong to the G-protein-coupled receptors. From a pharmacological point of view, the ('EDG-like') LPA1-3 receptors have attracted much attention, therefore we have also been focusing in our study on these subtypes. The LPA1receptors are widely expressed in the human body; interestingly, LPA1 might have a role in the pathomechanism of obesity.

Novel arylalkenylpropargylamines as neuroprotective, potent, and selective monoamine oxidase B inhibitors for the treatment of Parkinson's disease.

To develop novel neuroprotective agents, a library of novel arylalkenylpropargylamines was synthesized and tested for inhibitory activities against monoamine oxidases. From this, a number of highly potent and selective monoamine oxidase B inhibitors were identified. Selected compounds were also tested for neuroprotection in in vitro studies with PC-12 cells treated with 6-OHDA and rotenone, respectively.

Preparation of neuroprotective condensed 1,4-benzoxazepines by regio- and diastereoselective domino Knoevenagel-[1,5]-hydride shift cyclization reaction.

Condensed O,N-heterocycles containing tetrahydro-1,4-benzoxazepine and tetrahydroquinoline moieties were prepared by a regio- and diastereoselective domino Knoevenagel-[1,5]-hydride shift cyclization reaction of a 4-aryl-2-phenyl-1,4-benzoxazepine derivative obtained from flavanone. The relative configuration of products were determined by the correlation of (3) J H,H coupling data with the geometry of major conformers accessed by DFT conformational analysis. Separated enantiomers of the products were characterized by HPLC-ECD data, which allowed their configurational assignment on the basis of TDDFT-ECD calculation of the solution conformers.

Drug repositioning for treatment of movement disorders: from serendipity to rational discovery strategies.

Movement disorders are a heterogeneous group of both common and rare neurological conditions characterized by abnormalities of motor functions and movement patterns. This work overviews recent successes and ongoing studies of repositioning relating to this disease group, which underscores the challenge of integrating the voluminous and heterogeneous findings required for making suitable drug repositioning decisions. In silico drug repositioning methods hold the promise of automated fusion of heterogeneous information sources, but the controllable, flexible and transparent incorporation of the expertise of medicinal chemists throughout the repositioning process remains an open challenge.

Semicarbazide-sensitive amine oxidase/vascular adhesion protein-1: a patent survey.

Introduction: Vascular adhesion protein-1 (VAP-1)/semicarbazide-sensitive amine oxidase (SSAO) is an adhesion protein involved in leukocyte trafficking and inflammatory processes, with a special amine oxidase activity. Inhibitors have been mainly developed for treating chronic inflammatory disorders. The utility of inhibitors as antiangiogenic agents in ophthalmological and oncological diseases is currently under evaluation.

SSAO substrates exhibiting insulin-like effects in adipocytes as a promising treatment option for metabolic disorders.

Background: Benzylamine exerts insulin-like effects in adipocytes (e.g., glucose uptake and antilipolysis) and improves glucose handling in rodents.

Molecular modelling of subtypes (alpha(2A), alpha(2B) and alpha(2C)) of alpha(2)-adrenoceptors: a comparative study.

The therapeutic usefulness of current agents that activate the three alpha(2)-adrenoceptors, alpha(2A), alpha(2B) and alpha(2C) is limited by their lack of subtype selectivity. One approach to the development of subtype-selective agents is the in silico docking of potential ligands to the receptors in quantitative molecular modeling studies. Because the crystal structure of the alpha(2)-adrenoceptors is not known, we used homology modeling based on the published structure of bovine rhodopsin.

Utility of cyclodextrins in the formulation of genistein part 1. Preparation and physicochemical properties of genistein complexes with native cyclodextrins.

Isoflavones are suitable guest molecules for inclusion complex formation with cyclodextrins (CDs). The molecular encapsulation with CDs results in a solid, molecularly dispersed form and in a significantly improved aqueous solubility of isoflavones. Genistein, a key isoflavone constituent of Ononidis spinosae radix was found to form a supramolecular, non-covalent inclusion complex with both beta-cyclodextrin (beta-CD) and gamma-cyclodextrin (gamma-CD), while it did not form a stable complex with alpha-CD.

Modeling the human oxytocin receptor for drug discovery efforts.

The oxytocin receptor belongs to class A receptors within the great family of G protein-coupled receptors. The endogenous ligand oxytocin is a nonapeptide hormone that induces the uterine contractions at parturition and is used to induce the labor. The peptide oxytocin and, even more, its non-peptide antagonist, could be valuable tools in tocolysis.

3D QSAR models for alpha2a-adrenoceptor agonists.

Three-dimensional structure-activity relationship studies of alpha2a-adrenoceptor agonists were carried out by Distance Comparison (DISCOthech) and Comparative Molecular Field Analysis (CoMFA) methods to define the pharmacophore and a quantitative model, respectively, of this class of compounds. The statistical validation of the CoMFA model indicates its high predictive performance for binding affinities of new alpha2a-adrenoceptor agonists.

Lipophilicity of aminopyridazinone regioisomers.

Ten pairs of pyridazinone regioisomers were prepared, and their lipophilicity was described by the logarithm of the octanol/water partition coefficient (log P) determined experimentally and calculated with prediction methods. The 4- and 5-(substituted amino)-3(2H)-pyridazinone regioisomers were synthesized by nucleophilic substitution of one of the chloro atoms of 4,5-dichloro-2-methyl-3(2H)-pyridazinone or its 6-nitro derivative. Structures of new compounds were proven by spectroscopic methods.