Three-dimensional quantitative structure-activity relationships for a large series of potent antitubercular agents

Comparative molecular field analysis (CoMFA) studies were conducted on a series of 100 isoniazid derivatives as anti-tuberculosis agents using two receptor-independent structural data set alignment strategies: (1) rigid-body fit, and (2) pharmacophore-based. Significant cross-validated correlation coefficients were obtained (CoMFA(1), q(2) = 0,75 and CoMFA(2), q(2) = 0.74), indicating the potential of the models for untested compounds. The models were then used to predict the inhibitory potency of 20 test set compounds that were not included in the training set, and the predicted values were in good agreement with the experimental results.

Quantitative structure-activity studies on a series of migrastatin analogs as inhibitors of cancer cell metastasis

Migrastatin, a macrolide natural product, and its structurally related analogs are potent inhibitors of cancer cell metastasis, invasion and migration. In the present work, a specialized fragment-based method was employed to develop QSAR models for a series of migrastatin and isomigrastatin analogs. Significant correlation coefficients were obtained (best model, q(2) = 0.76 and r(2) = 0.91) indicating that the QSAR models possess high internal consistency. The best model was then used to predict the potency of an external test set, and the predicted values were in good agreement with the experimental results (R(2) (pred) = 0.85). The final model and the corresponding contribution maps, combined with molecular modeling studies, provided important insights into the key structural features for the anticancer activity of this family of synthetic compounds based on natural products.

Structure-activity relationships for a class of selective inhibitors of the major cysteine protease from Trypanosoma cruzi

Chagas` disease is a parasitic infection widely distributed throughout Latin America, with devastating consequences in terms of human morbidity and mortality. Cruzain, the major cysteine protease from Trypanosoma cruzi, is an attractive target for antitrypanosomal chemotherapy. In the present work, classical two-dimensional quantitative structure-activity relationships (2D QSAR) and hologram QSAR (HQSAR) studies were performed on a training set of 45 thiosemicarbazone and semicarbazone derivatives as inhibitors of T. cruzi cruzain. Significant statistical models (HQSAR, q2=0.75 and r2=0.96; classical QSAR, q2=0.72 and r2=0.83) were obtained, indicating their consistency for untested compounds. The models were then used to evaluate an external test set containing 10 compounds which were not included in the training set, and the predicted values were in good agreement with the experimental results (HQSAR, [image omitted]=0.95; classical QSAR, [image omitted]=0.91), indicating the existence of complementary between the two ligand-based drug design techniques.

Comparative molecular field analysis of a series of inhibitors of HIV-1 protease

Several protease inhibitors have reached the world market in the last fifteen years, dramatically improving the quality of life and life expectancy of millions of HIV-infected patients. In spite of the tremendous research efforts in this area, resistant HIV-1 variants are constantly decreasing the ability of the drugs to efficiently inhibit the enzyme. As a consequence, inhibitors with novel frameworks are necessary to circumvent resistance to chemotherapy. In the present work, we have created 3D QSAR models for a series of 82 HIV-1 protease inhibitors employing the comparative molecular field analysis (CoMFA) method. Significant correlation coefficients were obtained (q(2) = 0.82 and r(2) = 0.97), indicating the internal consistency of the best model, which was then used to evaluate an external test set containing 17 compounds. The predicted values were in good agreement with the experimental results, showing the robustness of the model and its substantial predictive power for untested compounds. The final QSAR model and the information gathered from the CoMFA contour maps should be useful for the design of novel anti-HIV agents with improved potency.

Acridone alkaloids as potent inhibitors of cathepsin V

Cathepsin V is a lysosomal cysteine peptidase highly expressed in thymus, testis and corneal epithelium. Eleven acridone alkaloids were isolated from Swinglea glutinosa (Bl.) Merr. (Rutaceae), with eight of them being identified as potent and reversible inhibitors of cathepsin V (IC(50) values ranging from 1.2 to 3.9 mu M). Detailed mechanistic characterization of the effects of these compounds on the cathepsin V-catalyzed reaction showed clear competitive inhibition with respect to substrate, with dissociation constants (K(i)) in the low micromolar range (2, K(i) = 1.2 mu M; 6, K(i) = 1.0 mu M; 7, K(i) = 0.2 mu M; and 11, K(i) = 1.7 mu M). Molecular modeling studies provided important insight into the structural basis for binding affinity and enzyme inhibition. Experimental and computational approaches, including biological evaluation, mode of action assessment and modeling studies were successfully employed in the discovery of a small series of acridone alkaloid derivatives as competitive inhibitors of catV. The most potent inhibitor (7) has a K(i) value of 200 nM. (C) 2011 Elsevier Ltd. All rights reserved.

A new nitrosyl ruthenium complex: Synthesis, chemical characterization, in vitro and in vivo antitumor activities and probable mechanism of action

This study describes the synthesis of a new ruthenium nitrosyl complex with the formula [RuCl(2)NO(BPA)] [BPA = (2-hydroxybenzyl)(2-methylpyridyl)amine ion], which was synthesized and characterized by spectroscopy, cyclic voltammetry, X-ray crystallography, and theoretical calculation data. The biological studies of this complex included in vitro cytotoxic assays, which revealed its activity against two different tumor cell lines (HeLa and Tm5), with efficacy comparable to that of cisplatin, a metal-based drug that is administered in clinical treatment. The in vivo studies showed that [RuCl2NO(BPA)] is effective in reducing tumor mass. Also, our results suggest that the mechanism of action of [RuCl(2)NO(BPA)] includes binding to DNA, causing fragmentation of this biological molecule, which leads to apoptosis. (C) 2011 Elsevier Masson SAS. All rights reserved.

Discovery of New Inhibitors of Schistosoma mansoni PNP by Pharmacophore-Based Virtual Screening

Schistosomiasis is considered the second most important tropical parasitic disease, with severe socioeconomic consequences for millions of people worldwide. Schistosoma monsoni, one of the causative agents of human schistosomiasis, is unable to synthesize purine nucleotides de novo, which makes the enzymes of the purine salvage pathway important targets for antischistosomal drug development. In the present work, we describe the development of a pharmacophore model for ligands of S. mansoni purine nucleoside phosphorylase (SmPNP) as well as a pharmacophore-based virtual screening approach, which resulted in the identification of three thioxothiazolidinones (1-3) with substantial in vitro inhibitory activity against SmPNP. Synthesis, biochemical evaluation, and structure activity relationship investigations led to the successful development of a small set of thioxothiazolidinone derivatives harboring a novel chemical scaffold as new competitive inhibitors of SmPNP at the low-micromolar range. Seven compounds were identified with IC(50) values below 100 mu M. The most potent inhibitors 7, 10, and 17 with 1050 of 2, 18, and 38 mu M, respectively, could represent new potential lead compounds for further development of the therapy of schistosomiasis.

Pharmacophore-based 3D QSAR studies on a series of high affinity 5-HT(1A) receptor ligands

5-HT(1A) receptor antagonists have been employed to treat depression, but the lack of structural information on this receptor hampers the design of specific and selective ligands. In this study, we have performed CoMFA studies on a training set of arylpiperazines (high affinity 5-HT(1A) receptor ligands) and to produce an effective alignment of the data set, a pharmacophore model was produced using Galahad. A statistically significant model was obtained, indicating a good internal consistency and predictive ability for untested compounds. The information gathered from our receptor-independent pharmacophore hypothesis is in good agreement with results from independent studies using different approaches. Therefore, this work provides important insights on the chemical and structural basis involved in the molecular recognition of these compounds. (C) 2010 Elsevier Masson SAS. All rights reserved.

Structural basis for selective inhibition of purine nucleoside phosphorylase from Schistosoma mansoni: Kinetic and structural studies

Selectivity plays a crucial role in the design of enzyme inhibitors as novel antiparasitic agents, particularly in cases where the target enzyme is also present in the human host. Purine nucleoside phosphorylase from Schistosoma mansoni (SmPNP) is an attractive target for the discovery of potential antischistosomal agents. In the present work, kinetic studies were carried out in order to determine the inhibitory potency, mode of action and enzyme selectivity of a series of inhibitors of SmPNP. In addition, crystallographic studies provided important structural insights for rational inhibitor design, revealing consistent structural differences in the binding mode of the inhibitors in the active sites of the SmPNP and human PNP (HsPNP) structures. The molecular information gathered in this work should be useful for future medicinal chemistry efforts in the design of new inhibitors of SmPNP having increased affinity and selectivity. (C) 2010 Elsevier Ltd. All rights reserved.

A WAVELET-BASED SPEAKER VERIFICATION ALGORITHM

This paper presents a study on wavelets and their characteristics for the specific purpose of serving as a feature extraction tool for speaker verification (SV), considering a Radial Basis Function (RBF) classifier, which is a particular type of Artificial Neural Network (ANN). Examining characteristics such as support-size, frequency and phase responses, amongst others, we show how Discrete Wavelet Transforms (DWTs), particularly the ones which derive from Finite Impulse Response (FIR) filters, can be used to extract important features from a speech signal which are useful for SV. Lastly, an SV algorithm based on the concepts presented is described.

Fragment-guided approach to incorporating structural information into a CoMFA study: BACE-1 as an example

Alzheimer`s disease is an ultimately fatal neurodegenerative disease, and BACE-1 has become an attractive validated target for its therapy, with more than a hundred crystal structures deposited in the PDB. In the present study, we present a new methodology that integrates ligand-based methods with structural information derived from the receptor. 128 BACE-1 inhibitors recently disclosed by GlaxoSmithKline R&D were selected specifically because the crystal structures of 9 of these compounds complexed to BACE-1, as well as five closely related analogs, have been made available. A new fragment-guided approach was designed to incorporate this wealth of structural information into a CoMFA study, and the methodology was systematically compared to other popular approaches, such as docking, for generating a molecular alignment. The influence of the partial charges calculation method was also analyzed. Several consistent and predictive models are reported, including one with r (2) = 0.88, q (2) = 0.69 and r (pred) (2) = 0.72. The models obtained with the new methodology performed consistently better than those obtained by other methodologies, particularly in terms of external predictive power. The visual analyses of the contour maps in the context of the enzyme drew attention to a number of possible opportunities for the development of analogs with improved potency. These results suggest that 3D-QSAR studies may benefit from the additional structural information added by the presented methodology.

Wavelet-based cepstrum calculation

In this paper we present a new wavelet-based algorithm for low-cost computation of the cepstrum. It can be used for real time precise pitch determination in automatic speech and speaker recognition systems. Many wavelet families are examined to determine the one that works best. The results confirm the efficacy and accuracy of the proposed technique for pitch extraction. (C) 2008 Elsevier B.V. All rights reserved.

Relative entropy measures applied to healthy and pathological voice characterization

Nowadays, noninvasive methods of diagnosis have increased due to demands of the population that requires fast, simple and painless exams. These methods have become possible because of the growth of technology that provides the necessary means of collecting and processing signals. New methods of analysis have been developed to understand the complexity of voice signals, such as nonlinear dynamics aiming at the exploration of voice signals dynamic nature. The purpose of this paper is to characterize healthy and pathological voice signals with the aid of relative entropy measures. Phase space reconstruction technique is also used as a way to select interesting regions of the signals. Three groups of samples were used, one from healthy individuals and the other two from people with nodule in the vocal fold and Reinke`s edema. All of them are recordings of sustained vowel /a/ from Brazilian Portuguese. The paper shows that nonlinear dynamical methods seem to be a suitable technique for voice signal analysis, due to the chaotic component of the human voice. Relative entropy is well suited due to its sensibility to uncertainties, since the pathologies are characterized by an increase in the signal complexity and unpredictability. The results showed that the pathological groups had higher entropy values in accordance with other vocal acoustic parameters presented. This suggests that these techniques may improve and complement the recent voice analysis methods available for clinicians. (C) 2008 Elsevier Inc. All rights reserved.

Neoproterozoic geodynamic evolution of SW-Gondwana: a southern African perspective

Our current understanding of the tectonic history of the principal Pan-African orogenic belts in southwestern Africa, reaching from the West Congo Belt in the north to the Lufilian/Zambezi, Kaoko, Damara, Gariep and finally the Saldania Belt in the south, is briefly summarized. On that basis, possible links with tectono-stratigraphic units and major structures on the eastern side of the Rio de la Plata Craton are suggested, and a revised geodynamic model for the amalgamation of SW-Gondwana is proposed. The Rio de la Plata and Kalahari Cratons are considered to have become juxtaposed already by the end of the Mesoproterozoic. Early Neoproterozoic rifting led to the fragmentation of the northwestern (in today`s coordinates) Kalahari Craton and the splitting off of several small cratonic blocks. The largest of these ex-Kalahari cratonic fragments is probably the Angola Block. Smaller fragments include the Luis Alves and Curitiba microplates in eastern Brazil, several basement inliers within the Damara Belt, and an elongate fragment off the western margin, named Arachania. The main suture between the Kalahari and the Congo-So Francisco Cratons is suspected to be hidden beneath younger cover between the West Congo Belt and the Lufilian/Zambezi Belts and probably continues westwards via the Cabo Frio Terrane into the Goias magmatic arc along the Brasilia Belt. Many of the rift grabens that separated the various former Kalahari cratonic fragments did not evolve into oceanic basins, such as the Northern Nosib Rift in the Damara Belt and the Gariep rift basin. Following latest Cryogenian/early Ediacaran closure of the Brazilides Ocean between the Rio de la Plata Craton and the westernmost fragment of the Kalahari Craton, the latter, Arachania, became the locus of a more than 1,000-km-long continental magmatic arc, the Cuchilla Dionisio-Pelotas Arc. A correspondingly long back-arc basin (Marmora Basin) on the eastern flank of that arc is recognized, remnants of which are found in the Marmora Terrane-the largest accumulation of oceanic crustal material known from any of the Pan-African orogenic belts in the region. Corresponding foredeep deposits that emerged from the late Ediacaran closure of this back-arc basin are well preserved in the southern areas, i.e. the Punta del Este Terrane, the Marmora Terrane and the Tygerberg Terrane. Further to the north, present erosion levels correspond with much deeper crustal sections and comparable deposits are not preserved anymore. Closure of the Brazilides Ocean, and in consequence of the Marmora back-arc basin, resulted from a change in the Rio de la Plata plate motion when the Iapetus Ocean opened between the latter and Laurentia towards the end of the Ediacaran. Later break-up of Gondwana and opening of the modern South Atlantic would have followed largely along the axis of the Marmora back-arc basin and not along major continental sutures.

The position of the Amazonian Craton in supercontinents

This paper examines the extensive regions of Proterozoic accretionary belts that either formed most of the Amazonian Craton, or are marginal to its southeastern border. Their overall geodynamic significance is considered taking into account the paleogeographic reconstruction of Columbia, Rodinia and Gondwana. Amazonia would be part of Columbia together With Laurentia, North China and Baltica, forming a continuous, continental landmass linked by the Paleo- to Mesoproterozoic mobile belts that constitute large portions of it. The Rodinia supercontinent was formed in the Mesoproterozoic by the agglutination of the existing cratonic fragments, such as Laurentia and Amazonia, during contemporary continental collisions worldwide. The available paleomagnetic data suggest that Laurentia and Amazonia remained attached until at least 600 Ma. Since all other cratonic units Surrounding Laurentia have already rifted away by that time, the separation between Amazonia and Laurentia marks the final break-up of Rodinia with the opening of the lapetus ocean. (C) 2009 International Association for Gondwana Research. Published by Elsevier B.V. All rights reserved.