Molecular Modeling Methods in the Development of Affine and Specific Protein-Binding Agents.

High-affinity and specific agents are widely applied in various areas, including diagnostics, scientific research, and disease therapy (as drugs and drug delivery systems). It takes significant time to develop them. For this reason, development of high-affinity agents extensively utilizes computer methods at various stages for the analysis and modeling of these molecules.

The search for potential hypotensive peptides in the amino acid sequence of human renalase and their identification in proteolytic fragments of this protein.

Renalase (RNLS) is a secretory protein discovered in 2005. It plays an important role in the regulation of blood pressure. Studies by two independent laboratories have shown that administration of purified recombinant RNLS reduced blood pressure in experimental animals.

A community effort in SARS-CoV-2 drug discovery.

The COVID-19 pandemic continues to pose a substantial threat to human lives and is likely to do so for years to come. Despite the availability of vaccines, searching for efficient small-molecule drugs that are widely available, including in low- and middle-income countries, is an ongoing challenge. In this work, we report the results of an open science community effort, the "Billion molecules against COVID-19 challenge", to identify small-molecule inhibitors against SARS-CoV-2 or relevant human receptors.

AliNA - a deep learning program for RNA secondary structure prediction.

Nowadays there are numerous discovered natural RNA variations participating in different cellular processes and artificial RNA, e. g., aptamers, riboswitches.

Enhancing the Catalytic Activity of Thermo-Asparaginase from by a Double Mesophilic-like Mutation in the Substrate-Binding Region.

L-asparaginases (L-ASNases) of microbial origin are the mainstay of blood cancer treatment. Numerous attempts have been performed for genetic improvement of the main properties of these enzymes. The substrate-binding Ser residue is highly conserved in L-ASNases regardless of their origin or type.

Proteomic Profiling of Mouse Brain Pyruvate Kinase Binding Proteins: A Hint for Moonlighting Functions of PKM1?

Affinity-based proteomic profiling is widely used for the identification of proteins involved in the formation of various interactomes. Since protein-protein interactions (PPIs) reflect the role of particular proteins in the cell, identification of interaction partners for a protein of interest can reveal its function. The latter is especially important for the characterization of multifunctional proteins, which can play different roles in the cell.

Oxazolinyl derivatives of androst-16-ene as inhibitors of CYP17A1 activity and prostate carcinoma cells proliferation: Effects of substituents in oxazolinyl moiety.

Steroid derivatives modified with nitrogen containing heterocycles are known to inhibit activity of steroidogenic enzymes, decrease proliferation of cancer cells and attract attention as promising anticancer agents. Specifically, 2'-(3β-hydroxyandrosta-5,16-dien-17-yl)-4',5'-dihydro-1',3'-oxazole 1a potently inhibited proliferation of prostate carcinoma cells. In this study we synthesized and investigated five new derivatives of 3β-hydroxyandrosta-5,16-diene comprising 4'-methyl or 4'-phenyl substituted oxazolinyl cycle 1 (b-f).

New Positive TRPC6 Modulator Penetrates Blood-Brain Barrier, Eliminates Synaptic Deficiency and Restores Memory Deficit in 5xFAD Mice.

Synapse loss in the brain of Alzheimer's disease patients correlates with cognitive dysfunctions. Drugs that limit synaptic loss are promising pharmacological agents. The transient receptor potential cation channel, subfamily C, member 6 (TRPC6) regulates the formation of an excitatory synapse.

Approaches for increasing the electrocatalitic efficiency of cytochrome P450 3A4.

The electrochemically driven cytochrome P450 reactions have great promise as drug sensing device, new drug searching tool and bioreactor with broad synthetic application. In the present work, we proposed approaches for the increasing the efficiency of cytochrome P450 3A4 electrocatalysis, based on fine regulation and reproduction of nature hemeprotein catalytic cycle and electron transfer pathways on electrode. To analyze the comparative electrochemical and electrocatalytic activity, cytochrome P450 3A4 was immobilized on electrodes modified with a membrane-like synthetic surfactant, didodecyldimethylammonium bromide (DDAB).

[The interactions of abiraterone and its pharmacologically active metabolite D4A with cytochrome P450 2C9 (CYP2C9)].

Interactions of cytochrome P450 2C9 (CYP2C9) were studied with the antitumor drug abiraterone and its pharmacologically active metabolite D4A, promising as an agent for prostate cancer treatment. It was shown by absorption spectroscopy, that both investigated compounds induced spectral changes of CYP2C9, indicating interactions of the pyridine nitrogen atom with the heme iron ion of the active site of the enzyme, but interactions of the ligands with the enzyme could be mediated by a water molecule bound to the heme iron ion. Based on the spectral changes, the values of dissociation constants (KS) for complexes of abiraterone and D4A with CYP2C9 were calculated as 1.

New Genetic Bomb Trigger: Design, Synthesis, Molecular Dynamics Simulation, and Biological Evaluation of Novel BIBR1532-Related Analogs Targeting Telomerase against Non-Small Cell Lung Cancer.

Telomeres serve a critical function in cell replication and proliferation at every stage of the cell cycle. Telomerase is a ribonucleoprotein, responsible for maintaining the telomere length and chromosomal integrity of frequently dividing cells. Although it is silenced in most human somatic cells, telomere restoration occurs in cancer cells because of telomerase activation or alternative telomere lengthening.

Mechanisms of the Antiproliferative and Antitumor Activity of Novel Telomerase-Carbonic Anhydrase Dual-Hybrid Inhibitors.

Human (h) telomerase (TL; EC 2.7.7.

Impact of Wind Gust on High-Speed Characteristics of Polarization Mode Dispersion in Optical Power Ground Wire Cables.

Polarization mode dispersion is recognized as a key factor limiting optical transmission systems, particularly those fiber links that run at bit rates beyond 10 Gbps. In-line test and characterization of polarization mode dispersion are thus of critical importance to evaluate the quality of installed optical fibers that are in use for high-speed signal traffics. However, polarization-based effects in optical fibers are stochastic and quite sensitive to a range of environmental changes, including optical cable movements.

Mechanism of the Affinity-Enhancing Effect of Isatin on Human Ferrochelatase and Adrenodoxin Reductase Complex Formation: Implication for Protein Interactome Regulation.

Isatin (indole-2, 3-dione) is a non-peptide endogenous bioregulator exhibiting a wide spectrum of biological activity, realized in the cell via interactions with numerous isatin-binding proteins, their complexes, and (sub) interactomes. There is increasing evidence that isatin may be involved in the regulation of complex formations by modulating the affinity of the interacting protein partners. Recently, using Surface Plasmon Resonance (SPR) analysis, we have found that isatin in a concentration dependent manner increased interaction between two human mitochondrial proteins, ferrochelatase (FECH), and adrenodoxine reductase (ADR).

Interactions of galeterone and its 3-keto-Δ4 metabolite (D4G) with one of the key enzymes of corticosteroid biosynthesis - steroid 21-monooxygenase (CYP21A2).

We have investigated interactions of galeterone and its pharmacologically active metabolite - 3-keto-Δ4-galeterone (D4G) - with one of the key enzymes of corticosteroid biosynthesis - steroid 21-monooxygenase (CYP21A2). It was shown by absorption spectroscopy that both compounds induce type I spectral changes of CYP21A2. Spectral dissociation constants (K ) of complexes of CYP21A2 with galeterone or D4G were calculated as 3.

The interactions of a number of steroid-metabolizing cytochromes P450 with abiraterone D4A metabolite: spectral analysis and molecular docking.

The interactions of pharmacologically active 3-keto-Δ4-metabolite of anticancer drug abiraterone (D4A) with steroid-metabolizing cytochromes P450 (CYP51A1, CYP11A1, CYP19A1) was studied by absorption spectroscopy and molecular docking. Both abiraterone and D4A induce type I spectral changes of CYP51A1, one of the enzymes of cholesterol biosynthesis. We have revealed that D4A did not induce spectral changes of CYP11A1, the key enzyme of pregnenolone biosynthesis, unlike abiraterone (type II ligand of CYP11A1).

[Ligand-receptor binding kinetics in drug design].

Traditionally, the thermodynamic values of affinity are considered as the main criterion for the development of new drugs. Usually, these values for drugs are measured at steady concentrations of the receptor and ligand, which are differed from environment. Recent studies have shown that the kinetics of the process of drug binding to its receptor make significant contribution in the drug effectiveness.

The Introduction of Hydrazone, Hydrazide, or Azepane Moieties to the Triterpenoid Core Enhances an Activity Against .

Background: Triterpenoids exhibit a wide spectrum of antimicrobial activity.

Objective: The objective of this study was to synthesize a series of nitrogen derivatives based on lupane, oleanane, and ursane triterpenoids with high antitubercular activity.

Methods: Isonicotinoylhydrazones were prepared via the reaction of 3-oxotriterpenic acids or betulonic aldehyde with isoniazid (INH) in yields of 54-72%.

Functional and structural features of proteins associated with alternative splicing.

The alternative splicing is a mechanism increasing the number of expressed proteins and a variety of these functions. We uncovered the protein domains most frequently lacked or occurred in the splice variants. Proteins presented by several isoforms participate in such processes as transcription regulation, immune response, etc.

The Role of the Ω-Loop in Regulation of the Catalytic Activity of TEM-Type β-Lactamases.

Bacterial resistance to β-lactams, the most commonly used class of antibiotics, poses a global challenge. This resistance is caused by the production of bacterial enzymes that are termed β-lactamases (βLs). The evolution of serine-class A β-lactamases from penicillin-binding proteins (PBPs) is related to the formation of the Ω-loop at the entrance to the enzyme's active site.

Estimation of the inhibiting impact of abiraterone D4A metabolite on human steroid 21-monooxygenase (CYP21A2).

Abiraterone D4A metabolite, the product of 3β-hydroxysteroid dehydrogenase activity toward abiraterone, may serve as a potential antitumor agent for the treatment of prostate cancer. The main adverse effect of abiraterone is the disruption of corticosteroid biosynthesis, and the more pharmacologically active abiraterone D4A metabolite may have the same issues. We therefore estimated the inhibiting impact of the abiraterone D4A metabolite on one of the key corticosteroidogenic enzymes - human steroid 21-monooxygenase (CYP21A2).

New steroidal oxazolines, benzoxazoles and benzimidazoles related to abiraterone and galeterone.

Seven new oxazoline, benzoxazole and benzimidazole derivatives were synthesized from 3β-acetoxyandrosta-5,16-dien-17-carboxylic, 3β-acetoxyandrost-5-en-17β-carboxylic and 3β-acetoxypregn-5-en-21-oic acids. Docking to active site of human 17α-hydroxylase/17,20-lyase revealed that all oxazolines, as well as benzoxazoles and benzimidazoles comprising Δ could form stable complexes with enzyme, in which steroid moiety is positioned similarly to that of abiraterone and galeterone, and nitrogen atom coordinates heme iron, while 16,17-saturated benzoxazoles and benzimidazoles could only bind in a position where heterocycle is located nearly parallel to heme plane. Modeling of the interaction of new benzoxazole and benzimidazole derivatives with androgen receptor revealed the destabilization of helix 12, constituting activation function 2 (AF2) site, by mentioned compounds, similar to one induced by known antagonist galeterone.

In vitro interactions of abiraterone, erythromycin, and CYP3A4: implications for drug-drug interactions.

Potential drug-drug interactions of the antitumor drug abiraterone and the macrolide antibiotic erythromycin were studied at the stage of cytochrome P450 3A4 (CYP3A4) biotransformation. Using differential spectroscopy, we have shown that abiraterone is a type II ligand of CYP3A4. The dependence of CYP3A4 spectral changes on the concentration of abiraterone is sigmoidal, which indicates cooperative interactions of CYP3A4 with abiraterone; these interactions were confirmed by molecular docking.

The impact of long-distance mutations on the Ω-loop conformation in TEM type β-lactamases.

β-lactamases are hydrolytic enzymes primarily responsible for occurrence and abundance of bacteria resistant to β-lactam antibiotics. TEM type β-lactamases are formed by the parent enzyme TEM-1 and more than two hundred of its mutants. Positions for the known amino acid substitutions cover ∼30% of TEM type enzyme's sequence.