[Show abstract][Hide abstract] ABSTRACT: The malaria parasite Plasmodium goes through two life stages in the human host, a non-symptomatic liver stage (LS) followed by a blood stage with all clinical manifestation of the disease. In this study, we investigated a series of 2-alkynoic fatty acids (2-AFAs) with chain lengths between 14 and 18 carbon atoms for dual in vitro activity against both life stages. 2-Octadecynoic acid (2-ODA) was identified as the best inhibitor of Plasmodium berghei parasites with ten times higher potency (IC50=0.34μg/ml) than the control drug. In target determination studies, the same compound inhibited three Plasmodium falciparum FAS-II (PfFAS-II) elongation enzymes PfFabI, PfFabZ, and PfFabG with the lowest IC50 values (0.28-0.80μg/ml, respectively). Molecular modeling studies provided insights into the molecular aspects underlying the inhibitory activity of this series of 2-AFAs and a likely explanation for the considerably different inhibition potentials. Blood stages of P. falciparum followed a similar trend where 2-ODA emerged as the most active compound, with 20 times less potency. The general toxicity and hepatotoxicity of 2-AFAs were evaluated by in vitro and in vivo methods in mammalian cell lines and zebrafish models, respectively. This study identifies 2-ODA as the most promising antiparasitic 2-AFA, particularly towards P. berghei parasites.
[Show abstract][Hide abstract] ABSTRACT: Chemometric pattern recognition techniques were employed in order to obtain Structure-Activity Relationship (SAR) models relating the structures of a series of adenosine compounds to the affinity for glyceraldehyde 3-phosphate dehydrogenase of Leishmania mexicana (LmGAPDH). A training set of 49 compounds was used to build the models and the best ones were obtained with one geometrical and four electronic descriptors. Classification models were externally validated by predictions for a test set of 14 compounds not used in the model building process. Results of good quality were obtained, as verified by the correct classifications achieved. Moreover, the results are in good agreement with previous SAR studies on these molecules, to such an extent that we can suggest that these findings may help in further investigations on ligands of LmGAPDH capable of improving treatment of leishmaniasis.
International Journal of Molecular Sciences 01/2014; 15(2):3186-203. · 2.46 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mycobacterium tuberculosis InhA (MtInhA) is an attractive enzyme to drug discovery efforts due to its validation as an effective biological target for tuberculosis therapy. In this work, two different virtual-ligand-screening approaches were applied in order to identify new InhA inhibitors' candidates from a library of ligands selected from the ZINC database. First, a 3-D pharmacophore model was built based on 36 available MtInhA crystal structures. By combining structure-based and ligand-based information, four pharmacophoric points were designed to select molecules able to satisfy the binding features of MtInhA substrate-binding cavity. The second approach consisted in using four well established docking programs, with different search algorithms, to compare the binding mode and score of the selected molecules from the aforementioned library. After detailed analyses of the results, six ligands were selected for in vitro analysis. Three of these molecules presented a satisfactory inhibitory activity with IC50 values ranging from 24 (± 2) μM to 83 (± 5) μM. The best compound presented an uncompetitive inhibition mode to NADH and 2-trans-dodecenoyl-CoA substrates, with Ki values of 24 (± 3) μM and 20 (± 2) μM, respectively. These molecules were not yet described as antituberculars or as InhA inhibitors, making its novelty interesting to start efforts on ligand optimization in order to identify new effective drugs against Tuberculosis having InhA as a target. More studies are underway to dissect the discovered uncompetitive inhibitor interactions with MtInhA.
Journal of Chemical Information and Modeling 07/2013; · 4.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: YopH plays a relevant role in three pathogenic species of Yersinia. Due to its importance in the prevention of the inflammatory response of the host, this enzyme has become a valid target for the identification and development of new inhibitors. In this work, an in-house library of 283 synthetic compounds was assayed against recombinant YopH from Yersinia enterocolitica. From these, four chalcone derivatives and one sulfonamide were identified for the first time as competitive inhibitors of YopH with binding affinity in the low micromolar range. Molecular modeling investigations indicated that the new inhibitors showed similar binding modes, establishing polar and hydrophobic contacts with key residues of the YopH binding site.
European journal of medicinal chemistry 04/2013; 64C:35-41. · 3.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Quantitative structure-activity relationship (QSAR) studies were performed in order to identify molecular features responsible for the antileishmanial activity of 61 adenosine analogues acting as inhibitors of the enzyme glyceraldehyde 3-phosphate dehydrogenase of Leishmania mexicana (LmGAPDH). Density functional theory (DFT) was employed to calculate quantum-chemical descriptors, while several structural descriptors were generated with Dragon 5.4. Variable selection was undertaken with the ordered predictor selection (OPS) algorithm, which provided a set with the most relevant descriptors to perform PLS, PCR and MLR regressions. Reliable and predictive models were obtained, as attested by their high correlation coefficients, as well as the agreement between predicted and experimental values for an external test set. Additional validation procedures were carried out, demonstrating that robust models were developed, providing helpful tools for the optimization of the antileishmanial activity of adenosine compounds.
[Show abstract][Hide abstract] ABSTRACT: In an article recently published in Química Nova, entitled "Chemistry Without Borders" ("Química Sem Fronteiras") [Pinto, A. C.; Zucco, C.; Galembeck, F.; Andrade, J. B.; Vieira, P. C. Quim. Nova 2012, 35, 2092], the authors highlighted the important aspects of science and technology with special emphasis on the field of Chemistry and its contributions toward a more prosperous Brazil of future. As a second step in that direction, this article extends the discussion of a key issue for the country in the framework of the chemistry community through the so called position papers in strategic areas. This document is a part of the contribution of the Brazilian Chemical Society to the World Science Forum to be held in Rio de Janeiro in November 2013. In this context, the present paper provides a brief discussion on neglected tropical diseases (NTDs) with emphasis on the current challenges and opportunities towards the development and evolution of the field. NTDs leads to illness, long-term disability or death, and has severe social, economic and psychological consequences for millions of men, women, and children worldwide. In most cases, the available treatments are inadequate and extremely limited in terms of efficacy and safety, leading to an urgent demand for new drugs. In addition to the traditional challenges involved in any drug discovery process, it is widely recognized that there is an innovation gap and a lack of investment for research and development (R&D) in the area of NTDs. In the last few decades, methods toward combating, eradication, prevention, and treatment of NTDs have been repeatedly emphasized in the major international agendas. Developments in these strategies and alliances have continued to have an essential impact, particularly in the area of drug discovery, both in Brazil and globally and should be encouraged and supported. Several examples of international activities dedicated to the reduction of the devastating global impact of NTDs can be provided. Despite the beneficial developments in the past 30 years, NTDs continue to devastate poor communities in remote and vulnerable areas, in large part, due to market failures and public policies. Recent studies have shown that among 756 new drugs approved between 2000 and 2011, only four new chemical entities (NCEs) were identified for the treatment of malaria, while none were developed against NTDs or tuberculosis. Furthermore, only 1.4% of approximately 150,000 clinical trials were registered for neglected diseases, with a smaller number of trials for NCEs. Establishment and strengthening of global strategies involving the triad "governmentacademiaindustry" is fundamental to the success in R&D of new drugs for NTDs. National and international publicprivate initiatives that aim to create, encourage, and invest in R&D projects have been implemented and therefore are of utmost importance to successfully integrate Brazil into this new paradigm. It is essential to lay the foundation for mechanisms that will intensify investments in infrastructure, training, and qualification of personnel with an ultimate strategic vision that foresees continuity. Our research group has made significant contributions to the development of this field with the goal of forging new frontiers while tackling both current and future challenges that include indispensable elements such as innovation and integration.
Química Nova 12/2012; 36(10):1552-1556. · 0.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A quantitative structure-activity relationship analysis was employed to explore the relationship between the molecular structure of thiosemicarbazone analogues and the inhibition of the cysteine protease cruzain, a validated target for Chagas' disease treatment. A data set containing 53 thiosemicarbazone derivatives was used to produce a quantitative model for activity prediction of unknown compounds. Several electronic descriptors were obtained through DFT calculations, along with a large amount of Dragon descriptors. The ordered predictor selection (OPS) algorithm was employed to select the most relevant descriptors to perform PLS regressions. With this procedure, significant correlation coefficients (r 2 = 0.85, q 2 = 0.78) were achieved. Furthermore, predicted values for an external test set are in good agreement with the experimental results, indicating the potential of the model for untested compounds. Additional validation tests were carried out, indicating that a robust and reliable model was obtained to be used in the design of new thiosemicarbazones with improved cruzain inhibition potential.
[Show abstract][Hide abstract] ABSTRACT: Tuberculosis (TB) is a major infectious disease caused by Mycobacterium tuberculosis (Mtb). According to the World Health Organization (WHO), about 1.8 million people die from TB and 10 million new cases are recorded each year. Recently, a new series of naphthylchalcones has been identified as inhibitors of Mtb protein tyrosine phosphatases (PTPs). In this work, 100 chalcones were designed, synthesized, and investigated for their inhibitory properties against MtbPtps. Structure–activity relationships (SAR) were developed, leading to the discovery of new potent inhibitors with IC50 values in the low-micromolar range. Kinetic studies revealed competitive inhibition and high selectivity toward the Mtb enzymes. Molecular modeling investigations were carried out with the aim of revealing the most relevant structural requirements underlying the binding affinity and selectivity of this series of inhibitors as potential anti-TB drugs.
Journal of Medicinal Chemistry 12/2011; 55(1). · 5.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The identification of promising hits and the generation of high quality leads are crucial steps in the early stages of drug discovery projects. The definition and assessment of both chemical and biological space have revitalized the screening process model and emphasized the importance of exploring the intrinsic complementary nature of classical and modern methods in drug research. In this context, the widespread use of combinatorial chemistry and sophisticated screening methods for the discovery of lead compounds has created a large demand for small organic molecules that act on specific drug targets. Modern drug discovery involves the employment of a wide variety of technologies and expertise in multidisciplinary research teams. The synergistic effects between experimental and computational approaches on the selection and optimization of bioactive compounds emphasize the importance of the integration of advanced technologies in drug discovery programs. These technologies (VS, HTS, SBDD, LBDD, QSAR, and so on) are complementary in the sense that they have mutual goals, thereby the combination of both empirical and in silico efforts is feasible at many different levels of lead optimization and new chemical entity (NCE) discovery. This paper provides a brief perspective on the evolution and use of key drug design technologies, highlighting opportunities and challenges.
[Show abstract][Hide abstract] ABSTRACT: Searching lead compounds for new antituberculosis drugs, the activity of synthetic sulfonamides and sulfonyl-hydrazones were assayed for their potential inhibitory activity towards a protein tyrosine phosphatase from Mycobacterium tuberculosis – PtpB. Four sulfonyl-hydrazones N-phenylmaleimide derivatives were active (compounds 14, 15, 19 and 21), and the inhibition of PtpB was found to be competitive with respect to the substrate p-nitrophenyl phosphate. Structure-based molecular docking simulations were performed and indicated that the new inhibitor candidates showed similar binding modes, filling the hydrophobic pocket of the protein by the establishment of van der Waals contacts, thereby contributing significantly to the complex stability.
Medicinal Chemistry Communication 06/2011; 2(6):500-504. · 2.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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, q2 = 0.76 and r2 = 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 (R2 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.
[Show abstract][Hide abstract] ABSTRACT: 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 μM). 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 μM; 6, K(i)=1.0 μM; 7, K(i)=0.2 μM; and 11, K(i)=1.7 μM). 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.
[Show abstract][Hide abstract] ABSTRACT: Schistosomiasis is considered the second most important tropical parasitic disease, with severe socioeconomic consequences for millions of people worldwide. Schistosoma mansoni , 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 μM. The most potent inhibitors 7, 10, and 17 with IC(50) of 2, 18, and 38 μM, respectively, could represent new potential lead compounds for further development of the therapy of schistosomiasis.
Journal of Chemical Information and Modeling 09/2010; 50(9):1693-705. · 4.30 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Tuberculosis (TB) is a major cause of morbidity and mortality throughout the world, and it is estimated that one-third of the world's population is infected with Mycobacterium tuberculosis. Among a series of tested compounds, we have recently identified five synthetic chalcones which inhibit the activity of M. tuberculosis protein tyrosine phosphatase A (PtpA), an enzyme associated with M. tuberculosis infectivity. Kinetic studies demonstrated that these compounds are reversible competitive inhibitors. In this work we also carried out the analysis of the molecular recognition of these inhibitors on their macromolecular target, PtpA, through molecular modeling. We observed that the predominant determinants responsible for the inhibitory activity of the chalcones are the positions of the two methoxyl groups at the A-ring, that establish hydrogen bonds with the amino acid residues Arg17, His49, and Thr12 in the active site of PtpA, and the substitution of the phenyl ring for a 2-naphthyl group as B-ring, that undergoes pi stacking hydrophobic interaction with the Trp48 residue from PtpA. Interestingly, reduction of mycobacterial survival in human macrophages upon inhibitor treatment suggests their potential use as novel therapeutics. The biological activity, synthetic versatility, and low cost are clear advantages of this new class of potential tuberculostatic agents.
[Show abstract][Hide abstract] ABSTRACT: The development of fast and reliable methods for the identification of new bioactive compounds is of utmost importance to boost the process of drug discovery and development. Immobilized enzyme reactors (IMERs), integrated with high performance liquid chromatography (HPLC), are attractive and versatile tools for screening collections consisting of natural products and synthetic small molecules. Standard kinetic parameters of the immobilized enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from both Trypanosoma cruzi de and human have been determined (T. cruzi: K-M(G3P) = 0.50 mmol L-1; K-M(NAD+) = 0.67 mmol L-1; humana: K-M(G3P) = 3.7 mmol L-1; K-M(NAD+) = 0.75 mmol L-1), and comparisons of these values with those of the parasite and human free enzymes indicate a decrease in the affinity for the immobilized system (T. cruzi: K-M(G3P) = 0.42 mmol L-1; K-M(NAD+) = 0.26 mmol L-1; humana: K-M(G3P) = 0.16 mmol L-1; K-M(NAD+) = 0.18 mmol L-1). Interestingly, despite the kinetic differences between the two systems, the immobilized GAPDHs retained the required structural requirements for molecular recognition and biological activity, increasing the stability the enzyme. In the present work, we described an integrated structural analysis which has provided important insights into the molecular basis underlying the effects of immobilization on the ligand-receptor interactions and consequent enzymatic activity and kinetics parameters.
Journal of the Brazilian Chemical Society 01/2010; 21(10):1845-1853. · 1.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Human parasitic diseases are the foremost threat to human health and welfare around the world. Trypanosomiasis is a very serious infectious disease against which the currently available drugs are limited and not effective. Therefore, there is an urgent need for new chemotherapeutic agents. One attractive drug target is the major cysteine protease from Trypanosoma cruzi, cruzain. In the present work, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) studies were conducted on a series of thiosemicarbazone and semicarbazone derivatives as inhibitors of cruzain. Molecular modeling studies were performed in order to identify the preferred binding mode of the inhibitors into the enzyme active site, and to generate structural alignments for the three-dimensional quantitative structure-activity relationship (3D QSAR) investigations. Statistically significant models were obtained (CoMFA, r2=0.96 and q2=0.78; CoMSIA, r2=0.91 and q2=0.73), indicating their predictive ability for untested compounds. The models were externally validated employing a test set, and the predicted values were in good agreement with the experimental results. The final QSAR models and the information gathered from the 3D CoMFA and CoMSIA contour maps provided important insights into the chemical and structural basis involved in the molecular recognition process of this family of cruzain inhibitors, and should be useful for the design of new structurally related analogs with improved potency.
[Show abstract][Hide abstract] ABSTRACT: Kinetic and crystallographic studies on the formation of the complex between iodoacetate and the enzyme glyceraldehyde-3-phosphate dehydrogenase from Trypanosoma cruzi were conducted in order to investigate the mechanistic and structural basis underlying enzyme inactivation. The crystallographic complex reveal important structural features useful for the design of novel inhibitors.
Letters in Drug Design & Discovery 03/2009; 6(3):210-214. · 0.85 Impact Factor