Júlio César Dias Lopes

Protein cutoff scanning: A comparative analysis of cutoff dependent and cutoff free methods for prospecting contacts in proteins

In this study, we carried out a comparative analysis between two classical methodologies to prospect residue contacts in proteins: the traditional cutoff dependent (CD) approach and cutoff free Delaunay tessellation (DT). In addition, two alternative coarse‐grained forms to represent residues were tested: using alpha carbon (CA) and side chain geometric center (GC). A database was built, comprising three top classes: all alpha, all beta, and alpha/beta. We found that the cutoff value at about 7.0 Å emerges as an important distance parameter. Up to 7.0 Å, CD and DT properties are unified, which implies that at this distance all contacts are complete and legitimate (not occluded). We also have shown that DT has an intrinsic missing edges problem when mapping the first layer of neighbors. In proteins, it may produce systematic errors affecting mainly the contact network in beta chains with CA. The almost‐Delaunay (AD) approach has been proposed to solve this DT problem. We found that even AD may not be an advantageous solution. As a consequence, in the strict range up to 7.0 Å, the CD approach revealed to be a simpler, more complete, and reliable technique than DT or AD. Finally, we have shown that coarse‐grained residue representations may introduce bias in the analysis of neighbors in cutoffs up to 6.8 Å, with CA favoring alpha proteins and GC favoring beta proteins. This provides an additional argument pointing to the value of 7.0 Å as an important lower bound cutoff to be used in contact analysis of proteins. Proteins 2009.

PHYSICO-CHEMICAL CHARACTERIZATION OF MEGLUMINE ANTIMONIATE

The leishmanicidal drug, meglumine antimoniate (MA), has been synthesized by the reaction of antimony oxyhydrated and N-methyl glucamine. Infrared and solid state NMR 13C analysis of MA and the ligand strongly suggests that antimony binds to N-methyl glucamine through the oxygen of C-3 carbon. Potentiometric titration indicated that, between pH 4.5 and 7.5, MA exists in the zwitterionic form

Thermodynamic evaluation and modeling of proton and water exchange associated with benzamidine and berenil binding to ß-trypsin

Serine-proteases are involved in vital processes in virtually all species. They are important targets for researchers studying the relationships between protein structure and activity, for the rational design of new pharmaceuticals. Trypsin was used as a model to assess a possible differential contribution of hydration water to the binding of two synthetic inhibitors. Thermodynamic parameters for the association of bovine beta-trypsin (homogeneous material, observed 23,294.4 +/- 0.2 Da, theoretical 23,292.5 Da) with the inhibitors benzamidine and berenil at pH 8.0, 25 degrees C and with 25 mM CaCl2, were determined using isothermal titration calorimetry and the osmotic stress method. The association constant for berenil was about 12 times higher compared to the one for benzamidine (binding constants are K = 596,599 +/- 25,057 and 49,513 +/- 2,732 M(-1), respectively; the number of binding sites is the same for both ligands, N = 0.99 +/- 0.05). Apparently the driving force responsible for this large difference of affinity is not due to hydrophobic interactions because the variation in heat capacity (DeltaCp), a characteristic signature of these interactions, was similar in both systems tested (-464.7 +/- 23.9 and -477.1 +/- 86.8 J K(-1) mol(-1) for berenil and benzamidine, respectively). The results also indicated that the enzyme has a net gain of about 21 water molecules regardless of the inhibitor tested. It was shown that the difference in affinity could be due to a larger number of interactions between berenil and the enzyme based on computational modeling. The data support the view that pharmaceuticals derived from benzamidine that enable hydrogen bond formation outside the catalytic binding pocket of beta-trypsin may result in more effective inhibitors.

The power metric: a new statistically robust enrichment-type metric for virtual screening applications with early recovery capability

A new metric for the evaluation of model performance in the field of virtual screening and quantitative structure–activity relationship applications is described. This metric has been termed the power metric and is defined as the fraction of the true positive rate divided by the sum of the true positive and false positive rates, for a given cutoff threshold. The performance of this metric is compared with alternative metrics such as the enrichment factor, the relative enrichment factor, the receiver operating curve enrichment factor, the correct classification rate, Matthews correlation coefficient and Cohen’s kappa coefficient. The performance of this new metric is found to be quite robust with respect to variations in the applied cutoff threshold and ratio of the number of active compounds to the total number of compounds, and at the same time being sensitive to variations in model quality. It possesses the correct characteristics for its application in early-recognition virtual screening problems.

Using linear algebra for protein structural comparison and classification.

In this article, we describe a novel methodology to extract semantic characteristics from protein structures using linear algebra in order to compose structural signature vectors which may be used efficiently to compare and classify protein structures into fold families. These signatures are built from the pattern of hydrophobic intrachain interactions using Singular Value Decomposition (SVD) and Latent Semantic Indexing (LSI) techniques. Considering proteins as documents and contacts as terms, we have built a retrieval system which is able to find conserved contacts in samples of myoglobin fold family and to retrieve these proteins among proteins of varied folds with precision of up to 80%. The classifier is a web tool available at our laboratory website. Users can search for similar chains from a specific PDB, view and compare their contact maps and browse their structures using a JMol plug-in.

Investigação eletroquímica e calorimétrica da interação de novos agentes antitumorais biscatiônicos com DNA

Biscationic amidines bind in the DNA minor groove and present biological activity against a range of infectious diseases. Two new biscationic compounds (bis-α,ω-S-thioureido, amino and sulfide analogues) were synthesized in good yields and fully characterized, and their interaction with DNA was also investigated. Isothermal titration calorimetry (ITC) was used to measure the thermodynamic properties of binding interactions between DNA and these ligands. A double stranded calf thymus DNA immobilized on an electrode surface was used to study the possible DNA-interacting abilities of these compounds towards dsDNA in situ. A remarkable interaction of these compounds with DNA was demonstrated and their potential application as anticancer agents was furthered.

H-1 and C-13 NMR of some alpha-halo derivatives of o-xylene

Abstract 13C and 1H NMR data for a series of α-halo derivatives of o-xylene are presented. A dynamic 1H NMR investigation of α,α,α′,α′-tetrabromo-o-xylene (5) was performed and the spectrum of the most stable conformer at 213 K is presented. The free energy of activation for the rotation of the CHBr2 groups in 5 are determined for the first time.

Synthesis by Click Reactions and Antiplasmodial Activity of Lupeol 1,2,3-Triazole Derivatives

Lupeol, a triterpene frequently found in Asteraceae plant species, showed moderate to low activity in different strains of Plasmodium falciparum, the most virulent malaria etiological agents. In this work, lupeol was isolated from Parahancornia fasciculata, a plant that is used to treat malaria in the Amazonia region. In the search of more activity lupeol derivatives, five new 1,2,3-triazole hybrid molecules were synthetized by copper-catalyzed azide-alkyne cycloaddition. The antiplasmodial activity of the semi-synthetic compounds were evaluated by the lactate dehydrogenase assay; the lupeol propargyl ether was the only one to disclosing increased activity (half maximal inhibitory concentration-IC50-62.0 ± 1.92 μmol L) in relation to lupeol (IC50 117.00 μmol L). Therefore, this work revealed a new class of interesting lupeol derivatives that can be obtained by linking electron donors to the hydroxy group at C-3.

SELECTIVE SULFENYLATIVE DESULFONYLATION OR DECARBALKOXYLATION OF α-SULFONYL MALONATES WITH DABCO OR Bu3N: REACTIVITY AND CONFORMATIONAL ANALYSIS

The study on reactivity of several α-substituted α-sulfonyl malonates toward 1,4-diazabicyclo[2.2.2]octane (DABCO) and Bu3N is described. The reactivity with DABCO revealed the possible competition between decarbalkoxylation and unexpected desulfonylation, depending on the α-substituent, because of sterical hindrance around the electrophilic centers (SO2 and CO2R). The derivatives with crowded α-substituents suffer selective desulfonylation, and a novel and efficient desulfonylation method can be proposed. The dependence of the reactivity of α-sulfonyl malonates on the sterical hindrance around the electrophilic centers is confirmed by conformational analysis (Macromodel/MM2* and Mopac/MP3). The carbanionic mechanism is proved because the corresponding protonated, deuterated, and sulfenylated products were obtained by addition of the corresponding electrophilic agents. Bu3N showed itself to be a novel selective decarbalkoxylation agent for any α-substituted α-sulfonyl malonate.

Estudos de relações estrutura-atividade quantitativas (QSAR) de bis-benzamidinas com atividade antifúngica

This paper describes 2D-QSAR and 3D-QSAR studies against Candida albicans and Cryptococcus neofarmans for a set of 20 bisbenzamidines. In the studies of 2D-QSAR with C. albicans it was obtained a correlation between log MIC-1 and lipolo component-Z (r2 = 0.68; Q2 = 0.51). In the case of C. neofarmans a correlation between log MIC-1 and lipolo component-Z and of Balaban index (r2 = 0.85; Q2 = 0.6) was obtained. 3D-QSAR studies using CoMFA showed that the steric fields contributed more to the predicted activities for Candida albicans (94.9%) and Cryptococcus neofarmans (97.9%).