Structure-activity relationships of fluorene compounds inhibiting HCV variants

Approximately 71 million people suffer from hepatitis C virus (HCV) infection worldwide. Persistent HCV infection causes liver diseases such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma, resulting in approximately 400,000 deaths annually. Effective direct-acting antiviral agents (DAAs) have been developed and are currently used for HCV treatment targeting the following three proteins: NS3/4A proteinase that cleaves the HCV polyprotein into various functional proteins, RNA-dependent RNA polymerase (designated as NS5B), and NS5A, which is required for the formation of double membrane vesicles serving as RNA replication organelles. At least one compound inhibiting NS5A is included in current HCV treatment regimens due to the high efficacy and low toxicity of drugs targeting NS5A. Here we report fluorene compounds showing strong inhibitory effects on GT 1b and 3a of HCV. Moreover, some compounds were effective against resistance-associated variants to DAAs. The structure-activity relationships of the compounds were analyzed. Furthermore, we investigated the molecular bases of the inhibitory activities of some compounds by the molecular docking method.11Ysciescopu

Fast conditional density estimation for quantitative structure-activity relationships

Many methods for quantitative structure-activity relationships (QSARs) deliver point estimates only, without quantifying the uncertainty inherent in the prediction. One way to quantify the uncertainy of a QSAR prediction is to predict the conditional density of the activity given the structure instead of a point estimate. If a conditional density estimate is available, it is easy to derive prediction intervals of activities. In this paper, we experimentally evaluate and compare three methods for conditional density estimation for their suitability in QSAR modeling. In contrast to traditional methods for conditional density estimation, they are based on generic machine learning schemes, more specifically, class probability estimators. Our experiments show that a kernel estimator based on class probability estimates from a random forest classifier is highly competitive with Gaussian process regression, while taking only a fraction of the time for training. Therefore, generic machine-learning based methods for conditional density estimation may be a good and fast option for quantifying uncertainty in QSAR modeling.http://www.aaai.org/ocs/index.php/AAAI/AAAI10/paper/view/181

Structure-activity relationships in nitrosamine carcinogenesis.

Statistically significant correlations have been demonstrated between carcinogenic activity, toxicity and number of carbons per molecule for an extensive set of nitrosamines. Such correlations, involving only bulk molecular properties indicate that the chemical nature of the alkyl substituents need not be the sole determinants of carcinogenic activity. These structure-activity relationships can be used to estimate carcinogenic activity with some degree of confidence

Structure–activity relationships of antibacterial peptides

Antimicrobial peptides play a crucial role in innate immunity, whose components are mainly peptide-based molecules with antibacterial properties. Indeed, the exploration of the immune system over the past 40 years has revealed a number of natural peptides playing a pivotal role in the defence mechanisms of vertebrates and invertebrates, including amphibians, insects, and mammalians. This review provides a discussion regarding the antibacterial mechanisms of peptide-based agents and their structure–activity relationships (SARs) with the aim of describing a topic that is not yet fully explored. Some growing evidence suggests that innate immunity should be strongly considered for the development of novel antibiotic peptide-based libraries. Also, due to the constantly rising concern of antibiotic resistance, the development of new antibiotic drugs is becoming a priority of global importance. Hence, the study and the understanding of defence phenomena occurring in the immune system may inspire the development of novel antibiotic compound libraries and set the stage to overcome drug-resistant pathogens. Here, we provide an overview of the importance of peptide-based antibacterial sources, focusing on accurately selected molecular structures, their SARs including recently introduced modifications, their latest biotechnology applications, and their potential against multi-drug resistant pathogens. Last, we provide cues to describe how antibacterial peptides show a better scope of action selectivity than several anti-infective agents, which are characterized by non-selective activities and non-targeted actions toward pathogens

Structure–activity relationships of opioid ligands

There are three different types of opioid receptor, namely mu, delta and kappa. Morphine and related clinically useful analgesics exert their actions through the mu opioid receptor. Such compounds represent a huge structural diversity, including both peptides and alkaloids. Nevertheless, there exists a common pharmacophore comprising two critical features, namely an amine nitrogen and an aromatic ring, usually with a hydroxyl substituent; the spatial relationship between them is also vital. [Continues.

Structure-activity relationships on cynnamoyl derivatives as inhibitors of p300 Histone acetyltransferase

Human p300 is a polyhedric transcriptional coactivator, playing a crucial role by acetylating histones on specific lysine residues. A great deal of evidences shows that p300 is involved in several diseases as leukemia, tumors and viral infection. Its involvement in pleiotropic biological roles and connections to diseases provide the rationale as to how its modulation could represent an amenable drug target. Several p300 inhibitors (HATi) have been described so far, but all suffer from low potency, lack of specificity or low cell-permeability, highlighting the need to find more effective inhibitors. Our cinnamoyl derivative, RC 56, was identified as active and selective p300 inhibitor, proving to be a good hit candidate to investigate the structure-activity relationship towards p300. Herein we describe the design, synthesis and biological evaluation of new HATi structurally related to our hit, investigating, moreover, the interactions between p300 and the best-emerged hits by means of induced fit docking and molecular dynamics simulations, gaining insight on the peculiar chemical features that influenced their activity toward the targeted enzyme

Carbohydrate-Based Surfactants: Structure-Activity Relationships

The aim of the present contribution is: (1) to review CBS in terms of structural classification based on their molecular size (mono-, oligo-, polymeric surfactants), geometry (standard, bipolar or bolaform, and gemini surfactants), and the nature of the polar headgroup (charged or not, cyclic or not), the apolar tail (number and length of alkyl chain), and the linker (amide, ester, ...) and/or the spacer; (2) to present systematically results on structure- activity relationships of uronic acid derivatives (UADs), a particular class of carbohydrate-based surfactants. These concern the impact of each structural entity including the polar headgroup (stereochemistry), apolar tail (chain length, number, and unsaturation), and linkage/spacer, on the performance of UADs to change surface properties, and possibly, to form and stabilize colloidal systems

Structure-activity relationships in Werner clathrates

Includes bibliographical references.The synthesis and characterization of a series of inorganic coordination compounds which, upon crystallization, have the ability to include solvent or guest molecules spatially within the lattice are reported. The compounds have the following general formula: [NiX2B4] - where X is isothiocyanate or bromine and B is 4-ethylpyridine, 4-vinylpiridine or 3,5-dimethylpyridine; [NiX2B2]n - where X is isothiocyanate, B is 2-aminopyridine and n indicates it is a polymer; [NiX2AB2]2 - where X is isothiocyanate, B is 3-aminopyridine (two of these four ligands in the dimer are bridging) and A is water. The various guest molecules have been carefully chosen, according to their point symmetry, which is a key factor in yielding structures of a particular type. The structures of seventeen compounds have been elucidated by single crystal x-ray analysis. The difficulty has been found to lie in refining disordered guest molecules. Other techniques employed in the initial characterization of these compounds are Microanalysis, Mass Spectrometry and UV/Visible Spectrophotometry. An intramolecular potential energy study on the [Ni(NCS)2(3,5-diMepy)4] complex reveals that the orthohydrogens on the 3,5-dimethylpyridine ligands control the conformation of the molecule. Packing densities and volume comparisons of the [Ni(NCS)2(4-Etpy)4] and [Ni(NCS)2(4-Vipy)4] complexes and their clathrates have been carried out. The exact sizes and shapes of the cavities in which the guest molecules are located in the x-ray crystal structures have been evaluated by both intermolecular potential energy and molecular volume calculations. Thermodynamic and spectroscopic properties of the [Ni(NCS)2(4-Etpy)4] and [Ni(NCS)2(4-Vipy)4] clathrates have been studied in both solution and the solid state. The techniques used are x-ray powder diffractometry, IR spectroscopy and Thermogravimetry (including Differential Thermal Analysis)