Design, Synthesis, In Silico Studies and In Vitro Evaluation of New Indole- and/or Donepezil-like Hybrids as Multitarget-Directed Agents for Alzheimer's Disease.

Alzheimer's disease (AD) is considered a complex neurodegenerative condition which warrants the development of multitargeted drugs to tackle the key pathogenetic mechanisms of the disease. In this study, two novel series of melatonin- and donepezil-based hybrid molecules with hydrazone () or sulfonyl hydrazone () fragments were designed, synthesized, and evaluated as multifunctional ligands against AD-related neurodegenerative mechanisms. Two lead compounds ( and ) exhibited a well-balanced multifunctional profile, demonstrating intriguing acetylcholinesterase (AChE) inhibition, promising antioxidant activity assessed by DPPH, ABTS, and FRAP methods, as well as the inhibition of lipid peroxidation in the linoleic acid system.

Evaluation of Acute and Sub-Acute Toxicity, Oxidative Stress and Molecular Docking of Two Nitrofuranyl Amides as Promising Anti-Tuberculosis Agents.

Tuberculosis (TB) remains a widespread infectious disease and one of the top 10 causes of death worldwide. Nevertheless, despite significant advances in the development of new drugs against tuberculosis, many therapies and preventive measures do not lead to the expected favorable health results for various reasons. The aim of this study was to evaluate the acute and sub-acute toxicity and oxidative stress of two selected nitrofuranyl amides with high in vitro antimycobacterial activity.

Generalized Net Model of the Foreign Object Principle and its Network Physiology Interpretations.

The Foreign Object Principle has been introduced in a formalized form for first time. Proven as a suitable tool for modelling of parallel processes flowing in real time, the generalized nets have been used for an interpretation of the Foreign Object Principle. It is illustrated by some examples from network physiology.

In Silico Identification of Multi-Target Ligands as Promising Hit Compounds for Neurodegenerative Diseases Drug Development.

The conventional treatment of neurodegenerative diseases (NDDs) is based on the "one molecule-one target" paradigm. To combat the multifactorial nature of NDDs, the focus is now shifted toward the development of small-molecule-based compounds that can modulate more than one protein target, known as "multi-target-directed ligands" (MTDLs), while having low affinity for proteins that are irrelevant for the therapy. The in silico approaches have demonstrated a potential to be a suitable tool for the identification of MTDLs as promising drug candidates with reduction in cost and time for research and development.

New Potential Pharmacological Targets of Plant-Derived Hydroxyanthraquinones from spp.

The increased use of polyphenols nowadays poses the need for identification of their new pharmacological targets. Recently, structure similarity-based virtual screening of DrugBank outlined pseudopurpurin, a hydroxyanthraquinone from spp., as similar to gatifloxacin, a synthetic antibacterial agent.

Development of New Antimycobacterial Sulfonyl Hydrazones and 4-Methyl-1,2,3-thiadiazole-Based Hydrazone Derivatives.

Fifteen 4-methyl-1,2,3-thiadiazole-based hydrazone derivatives - and sulfonyl hydrazones - were synthesized. They were characterized by H-NMR, C NMR, and HRMS. strain H37Rv was used to assess their antimycobacterial activity.

A Comprehensive Evaluation of Sdox, a Promising HS-Releasing Doxorubicin for the Treatment of Chemoresistant Tumors.

Sdox is a hydrogen sulfide (HS)-releasing doxorubicin effective in P-glycoprotein-overexpressing/doxorubicin-resistant tumor models and not cytotoxic, as the parental drug, in H9c2 cardiomyocytes. The aim of this study was the assessment of Sdox drug-like features and its absorption, distribution, metabolism, and excretion (ADME)/toxicity properties, by a multi- and transdisciplinary , , and approach. Doxorubicin was used as the reference compound.

Computational Analysis of Chemical Space of Natural Compounds Interacting with Sulfotransferases.

The aim of this study was to investigate the chemical space and interactions of natural compounds with sulfotransferases (SULTs) using ligand- and structure-based in silico methods. An in-house library of natural ligands (hormones, neurotransmitters, plant-derived compounds and their metabolites) reported to interact with SULTs was created. Their chemical structures and properties were compared to those of compounds of non-natural (synthetic) origin, known to interact with SULTs.

Cytotoxicity and Microbicidal Activity of Commonly Used Organic Solvents: A Comparative Study and Application to a Standardized Extract from .

The cytotoxicity and microbicidal capacity of seven organic solvents commonly applied for studying plant extracts and bioactive compounds were systematically investigated based on international standards. Four cell lines of normal (CCL-1, HaCaT) or tumor (A-375, A-431) tissue origin, seven bacterial and one fungal strain were used. The impact of the least toxic solvents in the determination of in vitro cytotoxicity was evaluated using a standardized extract from containing 54.

Dual SMO/BRAF Inhibition by Flavonolignans from .

Silymarin is the standardized extract from the fruits of (L.) Gaertn., a well-known hepatoprotectant and antioxidant.

A Free Web-Based Protocol to Assist Structure-Based Virtual Screening Experiments.

Chemical biology and drug discovery are complex and costly processes. In silico screening approaches play a key role in the identification and optimization of original bioactive molecules and increase the performance of modern chemical biology and drug discovery endeavors. Here, we describe a free web-based protocol dedicated to small-molecule virtual screening that includes three major steps: ADME-Tox filtering (via the web service FAF-Drugs4), docking-based virtual screening (via the web service MTiOpenScreen), and molecular mechanics optimization (via the web service AMMOS2 [Automatic Molecular Mechanics Optimization for in silico Screening]).

In vitro and in silico studies of the membrane permeability of natural flavonoids from Silybum marianum (L.) Gaertn. and their derivatives.

Background: In recent years the number of natural products used as pharmaceuticals, components of dietary supplements and cosmetics has increased tremendously requiring more extensive evaluation of their pharmacokinetic properties.

Purpose: This study aims at combining in vitro and in silico methods to evaluate the gastrointestinal absorption (GIA) of natural flavonolignans from milk thistle (Silybum marianum (L.) Gaertn.

Synthesis, antimycobacterial activity and docking study of 2-aroyl-[1]benzopyrano[4,3-c]pyrazol-4(1H)-one derivatives and related hydrazide-hydrazones.

A new convenient method for preparation of 2-aroyl-[1]benzopyrano[4,3-c]pyrazol-4(1H)-one derivatives 5b-g and coumarin containing hydrazide-hydrazone analogues 4a-e was presented. The antimycobacterial activity against reference strain Mycobacterium tuberculosis H37Rv and cytotoxicity against the human embryonic kidney cell line HEK-293 were tested in vitro. All compounds demonstrated significant minimum inhibitory concentrations (MIC) ranging 0.

AMMOS2: a web server for protein-ligand-water complexes refinement via molecular mechanics.

AMMOS2 is an interactive web server for efficient computational refinement of protein-small organic molecule complexes. The AMMOS2 protocol employs atomic-level energy minimization of a large number of experimental or modeled protein-ligand complexes. The web server is based on the previously developed standalone software AMMOS (Automatic Molecular Mechanics Optimization for in silico Screening).

ADME/Tox Properties and Biochemical Interactions of Silybin Congeners: In silico Study.

Silymarin, the active constituent of Silybum marianum (milk thistle), and its main component, silybin, are products with well-known hepatoprotective, cytoprotective, antioxidant, and chemopreventative properties. Despite substantial in vitro and in vivo investigations of these flavonolignans, their mechanisms of action and potential toxic effects are not fully defined. In this study we explored important ADME/Tox properties and biochemical interactions of selected flavonolignans using in silico methods.

Use of MR-based trabecular bone microstructure analysis at the distal radius for osteoporosis diagnostics: a study in post-menopausal women with breast cancer and treated with aromatase inhibitor.

Purpose: Treatment with aromatase inhibitor (AI) is recommended for post-menopausal women with hormone-receptor positive breast cancer. However, AI therapy is known to induce bone loss leading to osteoporosis with an increased risk for fragility fractures. The purpose of this study was to investigate whether changes of magnetic resonance (MR)-based trabecular bone microstructure parameters as advanced imaging biomarker can already be detected in subjects with AI intake but still without evidence for osteoporosis according to dual energy X-ray absorptiometry (DXA)-based bone mineral density (BMD) measurements as current clinical gold standard.

Functional state modelling approach validation for yeast and bacteria cultivations.

In this paper, the functional state modelling approach is validated for modelling of the cultivation of two different microorganisms: yeast () and bacteria (). Based on the available experimental data for these fed-batch cultivation processes, three different functional states are distinguished, namely primary product synthesis state, mixed oxidative state and secondary product synthesis state. Parameter identification procedures for different local models are performed using genetic algorithms.

Post-docking optimization and analysis of protein-ligand interactions of estrogen receptor alpha using AMMOS software.

Understanding protein-ligand interactions is a critical step in rational drug design/virtual ligand screening. In this work we applied the AMMOS_ProtLig software for post-docking optimization of estrogen receptor alpha complexes generated after virtual ligand screening protocol. Using MOE software we identified the ligand-receptor interactions in the optimized complexes at different levels of protein flexibility and compared them to the experimentally observed interactions.

AMMOS software: method and application.

Recent advances in computational sciences enabled extensive use of in silico methods in projects at the interface between chemistry and biology. Among them virtual ligand screening, a modern set of approaches, facilitates hit identification and lead optimization in drug discovery programs. Most of these approaches require the preparation of the libraries containing small organic molecules to be screened or a refinement of the virtual screening results.

Post-docking virtual screening of diverse binding pockets: comparative study using DOCK, AMMOS, X-Score and FRED scoring functions.

Most of the benchmark studies on docking-scoring methods reported in the last decade conclude that no single scoring function performs well across different protein targets. In this study a comparison of thirteen commonly used force field and empirical scoring functions as implemented in DOCK, AMMOS, X-Score and FRED is carried out on five proteins with diverse binding pockets. The performance is analyzed in relation to the physicochemical properties of the binding sites.

DG-AMMOS: a new tool to generate 3d conformation of small molecules using distance geometry and automated molecular mechanics optimization for in silico screening.

Background: Discovery of new bioactive molecules that could enter drug discovery programs or that could serve as chemical probes is a very complex and costly endeavor. Structure-based and ligand-based in silico screening approaches are nowadays extensively used to complement experimental screening approaches in order to increase the effectiveness of the process and facilitating the screening of thousands or millions of small molecules against a biomolecular target. Both in silico screening methods require as input a suitable chemical compound collection and most often the 3D structure of the small molecules has to be generated since compounds are usually delivered in 1D SMILES, CANSMILES or in 2D SDF formats.

AMMOS: Automated Molecular Mechanics Optimization tool for in silico Screening.

Background: Virtual or in silico ligand screening combined with other computational methods is one of the most promising methods to search for new lead compounds, thereby greatly assisting the drug discovery process. Despite considerable progresses made in virtual screening methodologies, available computer programs do not easily address problems such as: structural optimization of compounds in a screening library, receptor flexibility/induced-fit, and accurate prediction of protein-ligand interactions. It has been shown that structural optimization of chemical compounds and that post-docking optimization in multi-step structure-based virtual screening approaches help to further improve the overall efficiency of the methods.

[The effect of the intracerebroventricular administration of vasopressin on the arterial pressure and heart rate of Brattleboro and Long-Evans rats].

Vasopressin (VP) was administered in the lateral cerebral ventricles of homozygous rats with congenital diabetes insipidus of Brattleboro (BB) strain as well as of normal animals of Long Evans strain (LE). The following parameters were studied: the latent period for achievement of maximal pressor response in seconds (LP), absolute value of the increase in arterial pressure in comparison with the initial V mmHg (delta AP) and cardiac frequency (CF). The initial values of AP in BB were lower than those values found in LE (BB-9, 10 +/- 0.

[The hypertensive effect of vasopressin administered into the median eminence of the hypothalamus in rats].

Data about direct effect of vasopressin (VP) on the central arterial pressure (AP) orientated us to investigate the effect of its local administration in the median eminence (ME) of the hypothalamus in rats. For this purpose VP was administered in ME under micropellet form. AP was measured indirectly on the tail of rats up to 96th hour after operation.