Analysis and Visualization of Protein Channels, Tunnels, and Pores with MOLEonline and ChannelsDB 2.0.

Channels, tunnels, and pores serve as pathways for the transport of molecules and ions through protein structures, thus participating to their functions. MOLEonline ( https://mole.upol.

ChannelsDB 2.0: a comprehensive database of protein tunnels and pores in AlphaFold era.

ChannelsDB 2.0 is an updated database providing structural information about the position, geometry and physicochemical properties of protein channels-tunnels and pores-within deposited biomacromolecular structures from PDB and AlphaFoldDB databases. The newly deposited information originated from several sources.

Expanding the squaramide library as mycobacterial ATP synthase inhibitors: Innovative synthetic pathway and biological evaluation.

Mycobacterial ATP synthase is a validated therapeutic target for combating drug-resistant tuberculosis. Inhibition of this enzyme has been featured as an efficient strategy for the development of new antimycobacterial agents against drug-resistant pathogens. In this study, we synthesised and explored two distinct series of squaric acid analogues designed to inhibit mycobacterial ATP synthase.

Small change - big consequence: The impact of C15-C16 double bond in a D‑ring of estrone on estrogen receptor activity.

Estrogen receptor alpha (ER) is a key biomarker for breast cancer, and the presence or absence of ER in breast and other hormone-dependent cancers decides treatment regimens and patient prognosis. ER is activated after ligand binding - typically by steroid. 2682 steroid compounds were used in a molecular docking study to identify novel ligands for ER and to predict compounds that may show anticancer activity.

Novel heterocyclic hydroxamates as inhibitors of the mycobacterial zinc metalloprotease Zmp1 to probe its mechanism of function.

Mycobacterial zinc metalloprotease-1 (Zmp1) is an essential enzyme for intracellular survival and pathogenicity of Mycobacterium tuberculosis. However, the exact mechanism of function of this enzyme remains unclear. This paper examines the effect of novel organic molecules on the inhibition of Zmp1.

Metabolic interactions of benzodiazepines with oxycodone ex vivo and toxicity depending on usage patterns in an animal model.

Background And Purpose: Opioids and benzodiazepines are frequently combined in medical as well as in non-medical contexts. At high doses, such combinations often result in serious health complications attributed to pharmacodynamics interactions. Here, we investigate the contribution of the metabolic interactions between oxycodone, diazepam and diclazepam (a designer benzodiazepine) in abuse/overdose conditions through ex vivo, in vivo and in silico approaches.

Synthesis of dihydrotestosterone derivatives modified in the A-ring with (hetero)arylidene, pyrazolo[1,5-a]pyrimidine and triazolo[1,5-a]pyrimidine moieties and their targeting of the androgen receptor in prostate cancer.

One of the main directions of steroid research is the preparation of modified derivatives in which, in addition to changes in physicochemical properties, receptor binding is significantly altered, thus a bioactivity different from that of the parent compound predominates. In the frame of this work, 2-arylidene derivatives were first synthesized by regioselective modification of the A-ring of natural sex hormone, 5α-dihydrotestosterone (DHT). After Claisen-Schmidt condensations of DHT with (hetero)aromatic aldehydes in alkaline EtOH, heterocyclizations of the α,β-enones were performed with 3-amino-1,2,4-triazole, 3-aminopyrazole and 3-amino-5-methylpyrazole in the presence of t-BuOK in DMF to afford 7'-epimeric mixtures of A-ring-fused azolo-dihydropyrimidines, respectively.

Synthesis and Biological Activity of Brassinosteroid Analogues with a Nitrogen-Containing Side Chain.

Brassinosteroids are a class of plant hormones that regulate a broad range of physiological processes such as plant growth, development and immunity, including the suppression of biotic and abiotic stresses. In this paper, we report the synthesis of new brassinosteroid analogues with a nitrogen-containing side chain and their biological activity on . Based on molecular docking experiments, two groups of brassinosteroid analogues were prepared with short and long side chains in order to study the impact of side chain length on plants.

Novel thiazolidinedione-hydroxamates as inhibitors of Mycobacterium tuberculosis virulence factor Zmp1.

Zinc metalloprotease 1 (Zmp1) is an extracellular enzyme, which has been found essential for the intracellular survival and pathogenesis of Mycobacterium tuberculosis. In this work, we designed and synthesized a series of novel thiazolidinedione-hydroxamates and evaluated in silico their drug-likeness behavior. Then, their inhibitory properties towards a recombinant Zmp1 from Mycobacterium tuberculosis were analyzed by MALDI-TOF MS.

Synthesis of novel galeterone derivatives and evaluation of their in vitro activity against prostate cancer cell lines.

Prostate cancer is one of the main causes of male cancer-related deaths worldwide and the suppression of androgen receptor signalling is established as an effective strategy for the treatment. A series of galeterone analogues including several steroid-fused azacycles, as well as 17-(benzimidazol-1-ylimino), 16α-(benzimidazol-2-ylamino), and 16α-(benzothiazol-2-ylamino) steroid derivatives, were synthesized and tested against prostate cancer cell lines. Candidate compound 3f was shown to reduce AR-regulated transcription in a dose-dependent manner in nanomolar ranges and suppress expression of AR-regulated proteins Nkx3.

MolMeDB: Molecules on Membranes Database.

Biological membranes act as barriers or reservoirs for many compounds within the human body. As such, they play an important role in pharmacokinetics and pharmacodynamics of drugs and other molecular species. Until now, most membrane/drug interactions have been inferred from simple partitioning between octanol and water phases.

MOLEonline: a web-based tool for analyzing channels, tunnels and pores (2018 update).

MOLEonline is an interactive, web-based application for the detection and characterization of channels (pores and tunnels) within biomacromolecular structures. The updated version of MOLEonline overcomes limitations of the previous version by incorporating the recently developed LiteMol Viewer visualization engine and providing a simple, fully interactive user experience. The application enables two modes of calculation: one is dedicated to the analysis of channels while the other was specifically designed for transmembrane pores.

Discovery of N-(4-Amino-cyclohexyl)-9-cyclopentyl- N-(4-morpholin-4-ylmethyl-phenyl)- 9H-purine-2,6-diamine as a Potent FLT3 Kinase Inhibitor for Acute Myeloid Leukemia with FLT3 Mutations.

FLT3 tyrosine kinase is a potential drug target in acute myeloid leukemia (AML) because patients with FLT3-ITD mutations respond poorly to standard cytotoxic agents and there is a clear link between the disease and the oncogenic properties of FLT3. We present novel 2,6,9-trisubstituted purine derivatives with potent FLT3 inhibitory activity. The lead compound 7d displays nanomolar activity in biochemical assays and selectively blocks proliferation of AML cell lines harboring FLT3-ITD mutations, whereas other transformed and normal human cells are several orders of magnitude less sensitive.

Membrane-attached mammalian cytochromes P450: An overview of the membrane's effects on structure, drug binding, and interactions with redox partners.

Mammalian cytochromes P450 are an important class of enzymes involved in the biotransformation of many endo- and exogenous compounds. Cytochrome P450 isoforms are attached to the membrane of the endoplasmic reticulum or mitochondria, and their catalytic domains move along the membrane surface while being partially immersed in the membrane environment. Their active sites are connected to both the membrane and cytosolic environments via a complex network of access channels.

Synthesis of novel aryl brassinosteroids through alkene cross-metathesis and preliminary biological study.

A series of phenyl analogues of brassinosteroids was prepared via alkene cross-metathesis using commercially available styrenes and 24-nor-5α-chola-2,22-dien-6-one. All derivatives were successfully docked into the active site of BRI1 using AutoDock Vina. Plant growth promoting activity was measured using the pea inhibition biotest and Arabidopsis root sensitivity assay and then was compared with naturally occuring brassinosteroids.

RH421 binds into the ATP-binding site on the Na/K-ATPase.

The Na/K-ATPase plays a key role in ion transport across the plasma membrane of all animal cells. The voltage-sensitive styrylpyrimidium dye RH421 has been used in several laboratories for monitoring of Na/K-ATPase kinetics. It is known, that RH421 can interact with the enzyme and it can influence its activity at micromolar concentrations, but structural details of this interaction are only poorly understood.

Acetylated deoxycholic (DCA) and cholic (CA) acids are potent ligands of pregnane X (PXR) receptor.

The Pregnane X (PXR), Vitamin D (VDR) and Farnesoid X (FXR) nuclear receptors have been shown to be receptors of bile acids controlling their detoxification or synthesis. Chenodeoxycholic (CDCA) and lithocholic (LCA) acids are ligands of FXR and VDR, respectively, whereas 3-keto and acetylated derivates of LCA have been described as ligands for all three receptors. In this study, we hypothesized that oxidation or acetylation at position 3, 7 and 12 of bile acids DCA (deoxycholic acid), LCA, CA (cholic acid), and CDCA by detoxification enzymes or microbiome may have an effect on the interactions with bile acid nuclear receptors.

Exponential repulsion improves structural predictability of molecular docking.

Molecular docking is a powerful tool for theoretical prediction of the preferred conformation and orientation of small molecules within protein active sites. The obtained poses can be used for estimation of binding energies, which indicate the inhibition effect of designed inhibitors, and therefore might be used for in silico drug design. However, the evaluation of ligand binding affinity critically depends on successful prediction of the native binding mode.

Novel N-substituted indole Schiff bases as dual inhibitors of cyclooxygenase-2 and 5-lipoxygenase enzymes: Synthesis, biological activities in vitro and docking study.

Two new series of N-substituted indole derivatives 4a-l and 5a-h were synthesized. Their chemical structures were confirmed using spectroscopic tools including IR, (1)H NMR, (13)C NMR mass spectroscopy and elemental analyses. The results showed no significant cytotoxic activity on either cancer or normal human cells.

Novel thidiazuron-derived inhibitors of cytokinin oxidase/dehydrogenase.

Two new TDZ derivatives (HETDZ and 3FMTDZ) are very potent inhibitors of CKX and are promising candidates for in vivo studies. Cytokinin hormones regulate a wide range of essential processes in plants. Thidiazuron (N-phenyl-N'-1,2,3-thiadiazol-5-yl urea, TDZ), formerly registered as a cotton defoliant, is a well known inhibitor of cytokinin oxidase/dehydrogenase (CKX), an enzyme catalyzing the degradation of cytokinins.

Synthesis, biological evaluation and molecular modeling of a novel series of 7-azaindole based tri-heterocyclic compounds as potent CDK2/Cyclin E inhibitors.

From four molecules, inspired by the structural features of fascaplysin, with an interesting potential to inhibit cyclin-dependent kinases (CDKs), we designed a new series of tri-heterocyclic derivatives based on 1H-pyrrolo[2,3-b]pyridine (7-azaindole) and triazole heterocycles. Using a Huisgen type [3 + 2] cycloaddition as the convergent key step, 24 derivatives were synthesized and their biological activities were evaluated. Comparative molecular field analysis (CoMFA), based on three-dimensional quantitative structure-activity relationship (3D-QSAR) studies, was conducted on a series of 30 compounds from the literature with high to low known inhibitory activity towards CDK2/cyclin E and was validated by a test set of 5 compounds giving satisfactory predictive r(2) value of 0.

Characterization of a Pyrazolo[4,3-d]pyrimidine Inhibitor of Cyclin-Dependent Kinases 2 and 5 and Aurora A With Pro-Apoptotic and Anti-Angiogenic Activity In Vitro.

Selective inhibitors of kinases that regulate the cell cycle, such as cyclin-dependent kinases (CDKs) and aurora kinases, could potentially become powerful tools for the treatment of cancer. We prepared and studied a series of 3,5,7-trisubstituted pyrazolo[4,3-d]pyrimidines, a new CDK inhibitor scaffold, to assess their CDK2 inhibitory and antiproliferative activities. A new compound, 2i, which preferentially inhibits CDK2, CDK5, and aurora A was identified.

2,6,9-Trisubstituted purines as CRK3 kinase inhibitors with antileishmanial activity in vitro.

Here we describe the leishmanicidal activities of a library of 2,6,9-trisubstituted purines that were screened for interaction with Cdc2-related protein kinase 3 (CRK3) and subsequently for activity against parasitic Leishmania species. The most active compound inhibited recombinant CRK3 with an IC50 value of 162 nM and was active against Leishmania major and Leishmania donovani at low micromolar concentrations in vitro. Its mode of binding to CRK3 was investigated by molecular docking using a homology model.

Biological activities of new monohydroxylated brassinosteroid analogues with a carboxylic group in the side chain.

Thirteen monohydroxylated brassinosteroids analogues were synthesized and tested for their biological activity in plant and animal systems. The cytotoxic activity of the products was studied using human normal and cancer cell lines with 28-homocastasterone as positive control, their brassinolide type activity was established using the bean second-internode test with 24-epibrassinolide as standard.