[Show abstract][Hide abstract] ABSTRACT: Diapocynin has been regarded as the active principle of apocynin, which is the most used inhibitor of NADPH oxidase. Here we performed a comprehensive study of the interaction of diapocynin with human serum albumin (HSA). We found that diapocynin binds with higher efficacy to site I of HSA and its binding constant (8.5x105 mol-1L) was almost 100-fold higher compared to apocynin. By interacting with this chiral cavity of the protein, diapocynin became a chiral molecule, which was evidenced by its induced circular dichroism spectrum. The axial chirality was theoretically confirmed by searching the most stable conformations adopted by diapocynin using the Density Function Theory (DFT). The four minimum energy conformers, which presented dihedral angles of 58.00° and 302.00° (syn-aS and syn-aR enantiomers pair bearing 2,2'-dihydroxyl groups at the same side) and 132.86° and 227.14° (anti-aS and anti-aR enantiomers pair bearing 2,2'-dihydroxyl groups at opposite sides) were used as initial conformations for the docking simulations. The highest scored docking pose was obtained for site 1 and the dihedral angle resulted in 106.44°, i.e., an anti-aS chiral conformer. In conclusion, diapocynin is a strong ligand of HSA. An unprecedented combination of DFT calculation and docking simulation was used to explain the acquired chirality of diapocynin when bound to HSA.
[Show abstract][Hide abstract] ABSTRACT: HIV-1 protease is a key enzyme for viral maturation because it cleaves precursor polypeptides into mature structural and functional proteins. The introduction of protease inhibitors into therapy in the mid-1990s has dramatically changed the AIDS panorama worldwide. However, resistance to currently available protease inhibitors remains a serious challenge that must be overcome. Herein, we report a fragment-based QSAR study of a series of highly potent HIV-1 protease inhibitors, as well as the structural basis of their binding affinity. Hologram QSAR (HQSAR) analyses were performed, resulting in robust statistical models that consistently correlated the bioactivity profile with the two-dimensional molecular descriptors. The robustness of the best model was assessed based on the correlation coefficients (q(2) = 0.70 and r(2) = 0.90), as well as the prediction of the activity of an external test set (r(2)pred = 0.75). Structure-based molecular modeling studies were performed to investigate the binding mode of the best inhibitor in the active site of the enzyme. The HQSAR model and the structural findings provide valuable insights for the rational design of structurally related HIV-1 protease inhibitors.
[Show abstract][Hide abstract] ABSTRACT: Schistosomiasis, a neglected tropical disease caused by worms from the class Trematoda (genus Schistosoma), is a serious chronic condition that has been reported in approximately 80 countries. Nearly 250 million people are affected worldwide, mostly in the sub-Saharan Africa. Praziquantel, the mainstay of treatment, has been used for 30 years, and cases of resistance have been reported. The purpose of this perspective is to discuss current target-based molecular modeling strategies in schistosomiasis drug discovery. Advances in the field and the role played by the integration between computational modeling and experimental validation are also discussed. Finally, recent cases of the contribution of modern approaches in computational medicinal chemistry to the field are explored.
[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: Hybrid bioisoster derivatives from N-acylhydrazones and furoxan groups were designed with the objective of obtaining at least a dual mechanism of action: cruzain inhibition and nitric oxide (NO) releasing activity. Fifteen designed compounds were synthesized varying the substitution in N-acylhydrazone and in furoxan group as well. They had its anti-Trypanosoma cruzi activity in amastigotes forms, NO releasing potential and inhibitory cruzain activity evaluated. The two most active compounds (6, 14) both in the parasite amastigotes and in the enzyme contain the nitro group in para position of the aromatic ring. The permeability screening in Caco-2 cell and cytotoxicity assay in human cells were performed for those most active compounds and both showed to be less cytotoxic than the reference drug, benznidazole. Compound 6 was the most promising, since besides activity it showed good permeability and selectivity index, higher than the reference drug. Thereby the compound 6 was considered as a possible candidate for additional studies.
European Journal of Medicinal Chemistry 06/2014; 82C:418-425. DOI:10.1016/j.ejmech.2014.05.077 · 3.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The development of cruzain inhibitors has been driven by the urgent need to develop novel and more effective drugs for the treatment of Chagasꞌ disease. Herein, we report the lead optimization of a class of noncovalent cruzain inhibitors, starting from an inhibitor previously co-crystallized with the enzyme (Ki = 0.8 µM). With the goal of achieving a better understanding of the structure-activity relationships (SARs), we have synthesized and evaluated a series of over 40 analogues, leading to the development of a very promising competitive inhibitor (8r, IC50 = 200 nM, Ki = 82 nM). Investigation of the in vitro trypanocidal activity and preliminary cytotoxicity revealed the potential of the most potent cruzain inhibitors in guiding further medicinal chemistry efforts to develop drug candidates for Chagasꞌ disease.
[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 02/2014; 15(2):3186-203. DOI:10.3390/ijms15023186 · 2.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Chagas disease is a major cause of morbidity and death for millions of people in Latin America. The drugs currently available exhibit poor efficacy and severe side effects. Therefore, there is an urgent need for new, safe and effective drugs against Chagas disease. The vital dependence on glycolysis as energy source makes the glycolytic enzymes of Trypanosoma cruzi, the causative agent of Chagas disease, attractive targets for drug design. In this work, glyceraldehyde-3-phosphate dehydrogenase from T. cruzi (TcGAPDH) was employed as molecular target for the discovery of new inhibitors as hits. Results: Integrated protein-based pharmacophore and structure-based virtual screening approaches resulted in the identification of three hits from three chemical classes with moderate inhibitory activity against TcGAPDH. The inhibitors showed IC50 values in the high micromolar range. Conclusion: The new chemotypes are attractive molecules for future medicinal chemistry efforts aimed at developing new lead compounds for Chagas disease.
[Show abstract][Hide abstract] ABSTRACT: Background: Sleeping sickness is a major cause of death in Africa. Since no secure treatment is available, the development of novel therapeutic agents is urgent. In this context, the enzyme trypanothione reductase (TR) is a prominent molecular target that has been investigated in drug design for sleeping sickness. Results: In this study, comparative molecular field analysis models were generated for a series of Trypanosoma brucei TR inhibitors. Statistically significant results were obtained and the models were applied to predict the activity of external test sets, with good correlation between predicted and experimental results. We have also investigated the structural requirements for the selective inhibition of the parasite's enzyme over the human glutathione reductase. Conclusion: The quantitative structure-activity relationship models provided valuable information regarding the essential molecular requirements for the inhibitory activity upon the target protein, providing important insights into the design of more potent and selective TR inhibitors.
[Show abstract][Hide abstract] ABSTRACT: Medicinal chemistry is a multidisciplinary subject that integrates knowledge from a variety of fields of science, including, but not limited to, chemistry, biology, and physics. The area of drug design involves the cooperative work of scientists with a diverse range of backgrounds and technical skills, trying to tackle complex problems using an integration of approaches and methods. One important contribution to this field comes from physics through studies that attempt to identify and quantify the molecular interactions between small molecules (drugs) and biological targets (receptors), such as the forces that govern the interactions, the thermodynamics of the drug–receptor interactions, and so on. In this context, the interfaces of physics, medicinal chemistry, and drug design are of vital importance for the development of drugs that not only have the right chemistry but also the right intermolecular properties to interact at the macromolecular level, providing useful information about the principles and molecular mechanisms underlying the therapeutic action of drugs. This article highlights some of the most important connections between physics and medicinal chemistry in the design of new drugs.
[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; 53(9). DOI:10.1021/ci400202t · 4.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Drug resistance is a common concern for the development of novel antiviral, antimicrobial and anticancer therapies. To overcome this problem, several strategies have been developed, many of which involving the theme of this review, the use of structure-based drug design (SBDD) approaches. These include the successful design of new compounds that target resistant mutant proteins, as well as the development of drugs that target multiple proteins involved in specific biochemical pathways. Finally, drug resistance can also be considered in the early stages of drug discovery, through the use of strategies to delay the development of resistance. The purpose of this brief review is to underline the usefulness of SBDD approaches based on case studies, highlighting present challenges and opportunities in drug design.
Current pharmaceutical design 05/2013; DOI:10.2174/138161282005140214161949 · 3.29 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.