Autolysin E (AtlE), from Staphylococcus aureus, is a cell-walldegrading enzyme that is a potential drug target. It is a member of the glycoside hydrolase (GH) class, enzymes that commonly have either two catalytic residues and hydrolyze their substrates by inverting or retaining mechanisms or one catalytic residue and undergo retaining, substrate-assisted catalysis. Here, we address the catalytic mechanism of AtlE. Site-directed mutagenesis studies identified Glu138 as the only catalytic residue. Quantum mechanics/molecular mechanics (QM/MM) simulations of the possible reaction pathways suggest that hydrolysis proceeds via a retaining, water-assisted mechanism and an oxocarbenium ion like transition state. These results, on the basis of data from a member of the hydrolase GH73 family, support the hypothesis of the presence of an alternative catalytic mechanism in glycoside hydrolases, which can be considered in the design of future AtlE inhibitors.
COBISS.SI-ID: 31330087
Autolysin E (AtlE) is a cell wall degrading enzyme that catalyzes the hydrolysis of the ß-1,4-glycosidic bond between the Nacetylglucosamine and N-acetylmuramic acid units of the bacterial peptidoglycan. Using our recently determined crystal structure of AtlE from Staphylococcus aureus and a combination of pharmacophore modeling, similarity search, and molecular docking, a series of (Phenylureido)piperidinyl benzamides were identified as potential binders and surface plasmon resonance (SPR) and saturation-transfer difference (STD) NMR experiments revealed that discovered compounds bind to AtlE in a lower micromolar range. (phenylureido)piperidinyl benzamides are the first reported non-substrate-like compounds that interact with this enzyme and enable further study of the interaction of small molecules with bacterial AtlE as potential inhibitors of this target.
COBISS.SI-ID: 31627047
In the article, we described the architecture, available functions, and the usage of the program for the development of models using counter-propagation neural networks. The program facilitates validation of developed models and assessment of the reliability of predictions using applicability domain. Based on Kohonen map, which may show 2D structure of compounds, the user can assess the investigated property for a new compound using the property values of similar compounds in its neighbourhood (read-across). The usage of the program was presented in the article using examples from bio-concentration and acute fish toxicity modelling. The program enables development of QSAR models according to OCED principles, which enables their use for regulatory purposes. Open-access article is available in electronic form on the web page https://jcheminf.biomedcentral.com/articles/10.1186/s13321-017-0218-y.
COBISS.SI-ID: 6151706
Based on the previously published pyrazolopyridine-based hit compound for which negative allosteric modulation of both CXCR3 and CXCR4 receptors was disclosed, we designed, synthesized and biologically evaluated a set of novel, not only negative, but also positive allosteric modulators with preserved pyrazolopyridine core. Compound 9e is a dual negative modulator, inhibiting G protein activity of both receptors. For CXCR4 receptor para-substituted aromatic group of compounds distinguishes between negative and positive modulation. Para-methoxy substitution leads to functional antagonism, while para-chloro triggers agonism. Additionally, we discovered that chemotaxis is not completely correlated with G protein pathways. This is the first work in which we have on a series of compounds successfully demonstrated that it is possible to produce selective as well as dual-acting modulators of chemokine receptors, which is very promising for future research in the field of discovery of selective or dual modulators of chemokine receptors.
COBISS.SI-ID: 4504177
Effect of the addition of the pyrolytic product to aged bitumen was studied. Rejuvenator was prepared from scrap tire crumb modified pyrolytic condensate. Polycyclic aromatic hydrocarbons content in the pyrolysis condensate was kept low by applying relative low process temperature; the highest treatment temperature was 500oC. 50/70 penetration grade laboratory aged bitumen, prepared by using rolling thin film oven test (RTFOT) and accelerated pressure ageing vessel (PAV) procedure, was used as reference bitumen. The influence of various concentrations of rejuvenator (3%, 5%, 10% and 20%) on the aged and non-aged bitumen was evaluated by standard mechanical and rheological tests. Rheological measurements were performed in the intermediate range by dynamic shear rheometer (DSR) and in low temperature range with bending beam rheometer (BBR). The results confirmed the suitability of the rejuvenator for modification of the aged bitumen.
COBISS.SI-ID: 5924634
Antioxidants are important for maintaining the appropriate balance between oxidizing and reducing species in the body and thus preventing oxidative stress. Many natural compounds are being screened for their possible antioxidant activity. It was found that a mushroom pigment Norbadione A, which is a pulvinic acid derivative, shows an antioxidant activity; the same was found for other pulvinic acid derivatives and structurally related coumarines. Based on the results of in vitro studies performed on these compounds as a part of this study quantitative structure-activity relationship (QSAR) predictive models were constructed using multiple linear regression, counter-propagation artificial neural networks and support vector regression (SVR). The models have been developed in accordance with current QSAR guidelines, including the assessment of the models applicability domains. A new approach for the graphical evaluation of the applicability domain for SVR models is suggested. The developed models show sufficient predictive abilities for the screening of virtual libraries for new potential antioxidants.
COBISS.SI-ID: 5662490
Cathepsin K is a major drug target for osteoporosis and relatedbone disorders. Using a combination of virtual combinatorial chemistry, QSAR modeling, and molecular docking studies, a series of cathepsin K inhibitors based on N-(functionalized benzoyl)-homocycloleucylglycinonitrile scaffold was developed. In order to avoid previous problems of cathepsin K inhibitors associated with lysosomotropism of compounds with basic character that resulted in off-target effects, a weakly- to non-basic moiety was incorporated into the P3 position. Compounds 5, 6 and 9 were highly selective for cathepsin K when compared with cathepsins L and S with the Ki values in the 10-30 nM range. The kinetic studies revealed that the new compounds exhibited reversible tight binding to cathepsin K, while the X-ray structural studies showed covalent and noncovalent binding between the nitrile group and the catalytic cysteine (Cys25) site.
COBISS.SI-ID: 5755162
A comprehensive monography »Solved and Unsolved Problems of Structural Chemistry« published by CRC Press, Taylor & Francis group gives a perspective view on the most interesting problems in structural chemistry. It speaks about a number of overlooked, misunderstood, unrecognized or unaccepted, and unknown observations and findings in science. Solving a problem has been in a number of cases not the end, but the beginning of the end, as it has taken, or may take, additional time and efforts before solution is accepted.
COBISS.SI-ID: 17779545
This review article is, in a way, different from traditional review articles in that, besides being informative and reporting on the past published work in the area of graphical representation of complex biological data, it has an additional purpose in being provocative with respect to potentials of novelty in the future, rather than dwelling excessively on the accomplishments of the past. The review is factual; it is introductory and trying to be comprehensive with respect to its central topic—the graphical representation of proteins. Because it covers a topic, which may be viewed to be out of the mainstream avenue of comparative protein studies and an outline of events along a path not frequently trodden, we included sufficient introductory material on closely related topics of graphical representations of DNA and the secondary structure of RNA. It is not possible to study and understand proteins without studying and understanding DNA and RNA, so inclusion of material on DNA and RNA has been almost mandatory.
COBISS.SI-ID: 4616218
The cytotoxicity evaluation of various metal oxides nanoparticles (covered all metal oxides from the periodic system) was performed using computational approach based on neural network algorithm. The recommendations were done for the minimal number of cytotoxicity tests needs for evaluation of the large set of metal oxides with different oxidation states. The methodology is expected to be useful for potential hazard assessment of metal oxides nanoparticles and prioritisation for further testing and risk assessment.
COBISS.SI-ID: 6131738