Shape Theory Applied to Molecular Docking and Automatic Localization of Ligand Binding Pockets in Large Proteins

Automatic search of cavities and binding mode analysis between a ligand and a 3D protein receptor are challenging problems in drug design or repositioning. We propose a solution based on a shape theory theorem for an invariant coupled system of ligand–protein. The theorem provides a matrix representation with the exact formulas to be implemented in an algorithm. The method involves the following results: (1) exact formulae for the shape coordinates of a located-rotated invariant coupled system; (2) a parameterized search based on a suitable domain of van der Waals radii; (3) a scoring function for the discrimination of sites by measuring the distance between two invariant coupled systems including the atomic mass; (4) a matrix representation of the Lennard-Jones potential type 6–12 and 6–10 as the punctuation function of the algorithm for a molecular docking; and (5) the optimal molecular docking as a solution of an optimization problem based on the exploration of an exhaustive set of rotations. We apply the method in the xanthine oxidase protein with the following ligands: hypoxanthine, febuxostat, and chlorogenic acid. The results show automatic cavity detection and molecular docking not assisted by experts with meaningful amino acid interactions. The method finds better affinities than the expert software for known published cavities

An Engineered Lantibiotic Synthetase That Does Not Require a Leader Peptide on Its Substrate

Ribosomally synthesized and post-translationally modified peptides are a rapidly expanding class of natural products. They are typically biosynthesized by modification of a C-terminal segment of the precursor peptide (the core peptide). The precursor peptide also contains an N-terminal leader peptide that is required to guide the biosynthetic enzymes. For bioengineering purposes, the leader peptide is beneficial because it allows promiscuous activity of the biosynthetic enzymes with respect to modification of the core peptide sequence. However, the leader peptide also presents drawbacks as it needs to be present on the core peptide and then removed in a later step. We show that fusing the leader peptide for the lantibiotic lacticin 481 to its biosynthetic enzyme LctM allows the protein to act on core peptides without a leader peptide. We illustrate the use of this methodology for preparation of improved lacticin 481 analogues containing non-proteinogenic amino acids

Synthesis of Cyclic and Cage Borosilicates Based on Boronic Acids and Acetoxysilylalkoxides. Experimental and Computational Studies of the Stability Difference of Six- and Eight-Membered Rings

A series of borosilicates was synthesized, where the structure of the borosilicate core was easily modulated using two strategies: blocking of condensation sites and controlling the stoichiometry of the reaction. Thus, on the one hand, the condensation of phenylboronic or 3-hydroxyphenylboronic acid with diacetoxysilylalkoxide [(^<i>t</i>BuO)­(Ph₃CO)­Si­(OAc)₂] led to the formation of borosilicates (^<i>t</i>BuO)­(Ph₃CO)­Si­{(μ-O)­BPh}₂(μ-O) (<b>1</b>), [{(^<i>t</i>BuO)­(Ph₃CO)­Si­(μ-O)­BPh­(μ-O)}₂] (<b>2</b>), and [{(^<i>t</i>BuO)­(Ph₃CO)­Si­(μ-O)­B­(3-HOPh)­(μ-O)}₂] (<b>3</b>) with a cyclic inorganic B₂SiO₃ or B₂Si₂O₄ core, respectively. On the other hand, the reaction of phenylboronic acid with triacetoxysilylalkoxide (Ph₃CO)­Si­(OAc)₃ in 3:2 ratio resulted in the formation of a cagelike structure [{(Ph₃CO)­Si­(μ-O)₂BPh­(μ-O)}₂] (<b>4</b>) with B₄Si₄O₁₀ core, while the reaction of the boronic acid with silicon tetraacetate generated an unusual 1,3-bis­(acetate)-1,3-diphenyldiboraxane PhB­(μ-O)­(μ-O,O′-OAc)₂BPh (<b>5</b>). Additionally, compound <b>1</b> was used to evaluate the possibility to form N→B donor–acceptor bond between the boron atom in the borosilicates and a nitrogen donor. Thus, coordination of <b>1</b> with piperazine yielded a tricyclic [{(^<i>t</i>BuO)­(Ph₃CO)­Si­(OBPh)₂(μ-O)}₂·C₄H₁₀N₂] compound <b>6</b> with two borosilicate rings bridged by a piperazine molecule. Finally, the processes involved in the formation of the six- and eight-membered rings (B₂SiO₃ and B₂Si₂O₄) in compounds <b>1</b> and <b>2</b> were explored using solution ¹H NMR studies and density functional theory calculations. These molecules represent to the best of our knowledge first examples of cyclic molecular borosilicates containing SiO₄ units

Efficacy of a Binuclear Cyclopalladated Compound Therapy for cutaneous leishmaniasis in the murine model of infection with Leishmania amazonensis and its inhibitory effect on Topoisomerase 1B

Leishmaniasis is a disease found throughout the (sub)tropical parts of the world caused by protozoan parasites of the Leishmania genus. Despite the numerous problems associated with existing treatments, pharmaceutical companies continue to neglect the development of better ones. The high toxicity of current drugs combined with emerging resistance makes the discovery of new therapeutic alternatives urgent. Here we report the evaluation of a binuclear cyclopalladated complex containing Pd(II) and N,N' -dimethylbenzylamine (Hdmba) against Leishmania amazonensis. The compound [Pd(dmba)(μ-N3)]2 (CP2) inhibits promastigote growth (IC50 = 13.2 ± 0.7 μM) and decreases the proliferation of intracellular amastigotes in in vitro incubated macrophages (IC50 = 10.2 ± 2.2 μM) without a cytotoxic effect when tested against peritoneal macrophages (CC50 = 506.0 ± 10.7 μM). Additionally, CP2 was also active against T. cruzi intracellular amastigotes (IC50 = 2.3 ± 0.5 μM, Selective Index = 225), an indication of its potential for use in Chagas disease therapy. In vivo assays using L. amazonensis-infected BALB/c showed an 80% reduction in parasite load when compared to infected and non-treated animals. Also, compared to amphotericin B treatment, CP2 did not show any side effects, which was corroborated by the analysis of plasma levels of different hepatic and renal biomarkers. Furthermore, CP2 was able to inhibit Leishmania donovani topoisomerase 1B (Ldtopo1B), a potentially important target in this parasite

Structural Modularity of Unique Multicomponent Hydrogen-Bonded Organic Frameworks Based on Organosilanetriols and Silanediols as Molecular Building Blocks

In this study we examined the use of a new class of molecular building blocks with tetrahedral nodes based on organo-bis­(silanetriols) (1,4-[(HO)₃­SiOCEt₂]₂­C₆H₄ (<b>1</b>) and 4,4′-[(HO)₃­SiOCEt₂]₂-(1,1′-biphenyl) (<b>2</b>)) and organo-bis­(silanediol) (1,4-[{(HO)₂­(^<i>t</i>BuO)­Si}­OCEt₂]₂­C₆H₄ (<b>3</b>)) for the synthesis of multicomponent hydrogen-bonded organic frameworks (HOFs) with adjustable supramolecular patterns, and modular assembly. Thus, such reticular arrangements were readily obtained by the cocrystallization of bridged organosilanols (<b>1</b>, <b>2</b>, and <b>3</b>) with an organic diamine (1,4-diazabicyclo[2.2.2]­octane (<b>a</b>) or <i>trans</i>-1,2-bis­(4-pyridyl)­ethylene (<b>b</b>)) to yield the corresponding HOFs <b>1a</b>, <b>1b</b>, <b>2a</b>, <b>2b</b>, <b>3a</b>, and <b>3b</b>. Single-crystal X-ray diffraction analysis revealed that the dimensionality of the network, and by consequence, its porosity, can be easily engineered by means of the modulation of the central organic backbone of the organosilanol-based tectons, as well as by the Lewis basicity and the size of the corresponding organic diamine. In this context, it was found that although <b>1a</b> presents a nonporous arrangement, changing either the organic diamine as in <b>1b</b>, or the spacer’s size as in <b>2a</b>, it is possible to generate one-dimensional channels or zero-dimensional voids, respectively. Moreover, through gas sorption experiments, it was demonstrated that <b>1b</b> exhibits structural flexibility and permanent porosity with selective adsorption of CO₂ over N₂

Causal analysis of plasma IL-8 on carotid intima media thickness, a measure of subclinical atherosclerosis

No abstract available

Mechanism of Pyrogallol Red Oxidation Induced by Free Radicals and Reactive Oxidant Species. A Kinetic and Spectroelectrochemistry Study

Pyrogallol red (PGR) presents high reactivity toward reactive (radical and nonradical) species (RS). This property of PGR, together with its characteristic spectroscopic absorption in the visible region, has allowed developing methodologies aimed at evaluating the antioxidant capacity of foods, beverages, and human fluids. These methods are based on the evaluation of the consumption of PGR induced by RS and its inhibition by antioxidants. However, at present, there are no reports regarding the degradation mechanism of PGR, limiting the extrapolation to how antioxidants behave in different systems comprising different RS. In the present study, we evaluate the kinetics of PGR consumption promoted by different RS (peroxyl radicals, peroxynitrite, nitrogen dioxide, and hypochlorite) using spectroscopic techniques and detection of product by HPLC mass spectrometry. The same pattern of oxidation and spectroscopic properties of the products is observed, independently of the RS employed. Mass analysis indicates the formation of only one product identified as a quinone derivative, excluding the formation of peroxides or hydroperoxides and/or chlorinated compounds, in agreement with FOX’s assays and oxygen consumption experiments. Cyclic voltammetry, carried out at different pH’s, shows an irreversible oxidation of PGR, indicating the initial formation of a phenoxy radical and a second charge transfer reaction generating an ortho-quinone derivative. Spectroelectrochemical oxidation of PGR shows oxidation products with identical UV–visible absorption properties to those observed in RS-induced oxidation

Hydrotrope-Induced Inversion of Salt Effects on the Cloud Point of an Extended Surfactant

The authors report on the effects of electrolytes spanning a range of (NaOc, NaSCN, NaNO3, NaBr, NaCl, NaBu, NaOAc, Na2SO4, Na2HPO4, and Na2CO3) and (LiCl, NaCl, KCl, CsCl, and choline chloride) on the aq. soly. of an extended surfactant. The surfactant is anionic with a long hydrophobic tail as well as a significant fraction of propylene oxide groups and ethylene oxide groups (C12-14-PO16-EO2-SO4Na, X-AES). In the absence of electrolytes, X-AES exhibits a cloud-point temp. that decreases with increasing surfactant concn. After the addn. of salts to the surfactant solns., various shifts in the soly. curves are obsd. These shifts follow precisely the same Hofmeister series that is found for salting-in and salting-out effects in protein solns. In the presence of different concns. of sodium xylene sulfonate (SXS), the soly. of the surfactant increases. In this context, SXS can be considered to be a salting-in salt. However, when the electrolytes are added to an aq. soln. of X-AES and SXS the Hofmeister series reverses for divalent anions such as Na2SO4, Na2HPO4, and Na2CO3. Studies on the phase behavior and micelle structures using polarization microscopy, freeze-etch TEM, and NMR measurements indicate a dramatic change in the coexisting phases on the addn. of SXS