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The enzyme catalyzes single-strand breaks in DNA, which enables the topological changes that are required during fundamental cellular processes such as gene replication and transcription Pommier et al. The authors reported the discovery of a series of Ld Top1 inhibitors by using scaffold hopping and bioisosteric manipulations. The structure of known Top1 inhibitors such as camptothecin and edotecarin were used as the starting points for the molecular design.

The outline of the compounds was guided by molecular docking runs using the X-ray structures of Ld Top1 and the human ortholog. The structure of the ternary complex 5 - Ld Top1-DNA, which was predicted by molecular docking, revealed key structural features to the design of novel analogs. Considering the suitable antileishmanial activity and the lack of cytotoxicity, further studies on compound 5 would be useful for assessing other aspects, such as its pharmacokinetics profile.

Structure-based drug design approach to the discovery of a series of L. The strategy employing molecular docking led to the identification of compound 5 which shows suitable in vitro antiparasitic activity. Brindisi et al. Tryparedoxin peroxidase has been considered as a molecular target in SBDD studies since it reduces hydroperoxides produced by infected macrophages. This mechanism of detoxification is particularly attractive for drug design since it is unique to the parasite and essential for its survival Fiorillo et al. By using the X-ray structure of Leishmania major tryparedoxin peroxidase I Lm TXNPx , the authors run a molecular docking effort and selected a set of hits for experimental profiling.

The docking conformations were used for the design of a series of N,N-disubstituted 3-aminomethyl quinolones and some of them displayed activity against LmTXNPx. Calculation of physicochemical parameters demonstrated the drug-likeness of the designed series. In view of the activity and the drug-like properties of quinolone derivative 11 , this compound represents a suitable starting point for further studies aiming the development of novel drug candidates against leishmaniasis.

Structure-based virtual screening that resulted in the first report of a series of non-covalent L. The molecular docking approach led to the identification of aliphatic adamantyl derivative 11 which shows suitable activity against the enzyme. A variety of LBDD approaches have been recently reported in leishmaniasis drug discovery. These studies are frequently conducted in combination with experimental protocols and SBDD methods. One of these studies reports an approach to pursuing novel compounds based on their effects on cell metabolism Armitage et al.

Next, a principal component analysis PCA was applied to generate a model that assorts these compounds according to their putative mode of action. The authors demonstrated structural patterns involved in the modulation of different metabolic pathways and additionally, the role of physicochemical properties in the stimulation of individual biochemical routes. The study is very interesting, as it enables the classification of compound databases according to the most likely mechanism of action and biological outcomes.

It also provides a way to run mechanistic studies of compounds that are known to be active against Leishmania species, thus offering a guide for downstream experimental profiling. Ligand-based approach to classify compounds according to their mechanism of action. The effects of the dataset compounds on Leishmania metabolism were analyzed by capillary electrophoresis—mass spectrometry, and the data were used in a principal component analysis PCA. With the aid of QSAR modeling, Bhagat and coauthors described the synthesis and in vitro evaluation of 26 aminophosphonate derivatives Bhagat et al.

Six compounds 12—17 , Figure 7A displayed activity on L. The models provided useful insights for future efforts on the optimization of this series. The CoMFA contour maps indicated that adding an electronegative group at the para position and a bulky electropositive substituent at the meta position in ring A would improve biological activity. A A series of aminophosphonate derivatives as novel compounds featuring antiparasitic activity against L.

B Triazole and thiosemicarbazone hybrids 18 and 19 showed promising activity against L. In a recent study, Temraz et al. Out of the 17 evaluated molecules, most of them exhibited biological activity that is comparable or superior to that of the reference drug miltefosine. The most promising analogs, 18 and 19 , exhibited IC 50 values of On amastigotes, IC 50 values of 1.

The folate pathway was proposed as the target metabolic route, since folic acid reversed the antiparasitic activity. Considering the activity, selectivity, physicochemical and ADMET data, these triazole and thiosemicarbazone hybrids consist of promising lead compounds to be further investigated. In an investigation by Ashok et al. All compounds underwent QSPR studies for physicochemical profiling. Given the gathered activity, selectivity and physicochemical data, this series consists of appropriate starting points for further investigation.

Additional studies would be highly desirable for evaluating the in vivo reduction in parasite burden and hence, the potential of this series as novel drug candidates for leishmaniasis. B Cholesterol and deoxycholic acid derivatives 21 and 22 feature suitable activity against several Leishmania species. Steroid derivatives were described as novel antileishmanial agents in a recent report by da Trindade Granato et al. Out of the 16 synthesized analogs, cholesterol derivative 21 and some deoxycholic acid DOA derivatives proved active against Leishmania promastigotes Figure 8B.

Most DOAs were active against L. Treatment of L.

Additionally, the predictions indicated that this compound would have good blood-brain barrier permeation and would be susceptible to metabolic clearance by CYP3A4 enzymes. Further efforts to improve the in vitro activity of 22 and evaluate its in vivo efficacy would be worthwhile. A number of drug candidates are undergoing lead optimization studies and advanced in vivo preclinical profiling for leishmaniasis.

Some of them could reach the clinical development phase, which have recently been filled by evaluations of different treatment regimens and combinations of previously approved drugs. Despite these advances and outcomes, it is prudent to adopt a conservative mindset given the long path that these compounds will have to take until potential approval and the high attrition rates that characterize pharmaceutical research.

In this context, long-lasting efforts will be required to support state-of-the-art research programs that focus on the discovery of novel lead compounds for leishmaniasis.

Chemoinformatics

Such programs do exist today and have taken major advantage of the plentiful availability of data on Leishmania , as they move from trial-and-error to rational drug design. Current SBDD and LBDD campaigns have steadily contributed to rationalizing experimental data, thus providing effective insights into the design of optimized compounds. An important advance would be the validation of a higher number of molecular targets.

Opportunely, some research centers have put intense efforts into this issue by developing large-scale chemical genomics and target deconvolution expertise. Regardless of the challenges ahead, chemoinformatics have been an important tool to prospect and profile promising compounds.

Integrated Chemoinformatics Approaches Toward Epigenetic Drug Discovery

All authors listed have made a substantial, direct andintellectual contribution to the work, and approved it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Abongomera, C.

Drug discovery and development process

The initial effectiveness of liposomal amphotericin B AmBisome and miltefosine combination for treatment of visceral leishmaniasis in HIV co-infected patients in Ethiopia: a retrospective cohort study. PLoS Negl. Ansari, M. Recent advancement and treatment of leishmaniasis based on pharmacoinformatics approach: current and future outlook. Gene Rep. Armitage, E. Metabolic clustering analysis as a strategy for compound selection in the drug discovery pipeline for Leishmaniasis.

ACS Chem. Ashok, P. Berman, H. The protein data bank. Nucleic Acids Res. Bhagat, S. MedChemComm 5, — Brindisi, M. Structure-based discovery of the first non-covalent inhibitors of Leishmania major tryparedoxin peroxidase by high throughput docking. Casgrain, P. Cysteine peptidase B regulates Leishmania mexicana virulence through the modulation of GP63 expression. PLoS Pathog. Chen, C. A novel integrated framework and improved methodology of computer-aided drug design. Copeland, N.

Publication details

Leishmaniasis: treatment updates and clinical practice guidelines review. Cordeiro, A. Crystal structure of dihydroorotate dehydrogenase from Leishmania major. Biochimie 94, — Cramer, R.

Description

In view of the activity and the drug-like properties of quinolone derivative 11 , this compound represents a suitable starting point for further studies aiming the development of novel drug candidates against leishmaniasis. Structure-based virtual screening that resulted in the first report of a series of non-covalent L. The molecular docking approach led to the identification of aliphatic adamantyl derivative 11 which shows suitable activity against the enzyme.

A variety of LBDD approaches have been recently reported in leishmaniasis drug discovery. These studies are frequently conducted in combination with experimental protocols and SBDD methods. One of these studies reports an approach to pursuing novel compounds based on their effects on cell metabolism Armitage et al. Next, a principal component analysis PCA was applied to generate a model that assorts these compounds according to their putative mode of action.

Frontiers | Chemoinformatics Strategies for Leishmaniasis Drug Discovery | Pharmacology

The authors demonstrated structural patterns involved in the modulation of different metabolic pathways and additionally, the role of physicochemical properties in the stimulation of individual biochemical routes. The study is very interesting, as it enables the classification of compound databases according to the most likely mechanism of action and biological outcomes. It also provides a way to run mechanistic studies of compounds that are known to be active against Leishmania species, thus offering a guide for downstream experimental profiling.

Ligand-based approach to classify compounds according to their mechanism of action. The effects of the dataset compounds on Leishmania metabolism were analyzed by capillary electrophoresis—mass spectrometry, and the data were used in a principal component analysis PCA. With the aid of QSAR modeling, Bhagat and coauthors described the synthesis and in vitro evaluation of 26 aminophosphonate derivatives Bhagat et al.

Six compounds 12—17 , Figure 7A displayed activity on L.


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The models provided useful insights for future efforts on the optimization of this series. The CoMFA contour maps indicated that adding an electronegative group at the para position and a bulky electropositive substituent at the meta position in ring A would improve biological activity. A A series of aminophosphonate derivatives as novel compounds featuring antiparasitic activity against L.

B Triazole and thiosemicarbazone hybrids 18 and 19 showed promising activity against L. In a recent study, Temraz et al. Out of the 17 evaluated molecules, most of them exhibited biological activity that is comparable or superior to that of the reference drug miltefosine. The most promising analogs, 18 and 19 , exhibited IC 50 values of On amastigotes, IC 50 values of 1. The folate pathway was proposed as the target metabolic route, since folic acid reversed the antiparasitic activity.

Considering the activity, selectivity, physicochemical and ADMET data, these triazole and thiosemicarbazone hybrids consist of promising lead compounds to be further investigated. In an investigation by Ashok et al. All compounds underwent QSPR studies for physicochemical profiling. Given the gathered activity, selectivity and physicochemical data, this series consists of appropriate starting points for further investigation. Additional studies would be highly desirable for evaluating the in vivo reduction in parasite burden and hence, the potential of this series as novel drug candidates for leishmaniasis.

B Cholesterol and deoxycholic acid derivatives 21 and 22 feature suitable activity against several Leishmania species. Steroid derivatives were described as novel antileishmanial agents in a recent report by da Trindade Granato et al. Out of the 16 synthesized analogs, cholesterol derivative 21 and some deoxycholic acid DOA derivatives proved active against Leishmania promastigotes Figure 8B. Most DOAs were active against L. Treatment of L. Additionally, the predictions indicated that this compound would have good blood-brain barrier permeation and would be susceptible to metabolic clearance by CYP3A4 enzymes.

Further efforts to improve the in vitro activity of 22 and evaluate its in vivo efficacy would be worthwhile. A number of drug candidates are undergoing lead optimization studies and advanced in vivo preclinical profiling for leishmaniasis. Some of them could reach the clinical development phase, which have recently been filled by evaluations of different treatment regimens and combinations of previously approved drugs. Despite these advances and outcomes, it is prudent to adopt a conservative mindset given the long path that these compounds will have to take until potential approval and the high attrition rates that characterize pharmaceutical research.

In this context, long-lasting efforts will be required to support state-of-the-art research programs that focus on the discovery of novel lead compounds for leishmaniasis. Such programs do exist today and have taken major advantage of the plentiful availability of data on Leishmania , as they move from trial-and-error to rational drug design. Current SBDD and LBDD campaigns have steadily contributed to rationalizing experimental data, thus providing effective insights into the design of optimized compounds. An important advance would be the validation of a higher number of molecular targets.

Opportunely, some research centers have put intense efforts into this issue by developing large-scale chemical genomics and target deconvolution expertise. Regardless of the challenges ahead, chemoinformatics have been an important tool to prospect and profile promising compounds. All authors listed have made a substantial, direct andintellectual contribution to the work, and approved it for publication. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Abongomera, C. The initial effectiveness of liposomal amphotericin B AmBisome and miltefosine combination for treatment of visceral leishmaniasis in HIV co-infected patients in Ethiopia: a retrospective cohort study. PLoS Negl. Ansari, M. Recent advancement and treatment of leishmaniasis based on pharmacoinformatics approach: current and future outlook.

Gene Rep. Armitage, E. Metabolic clustering analysis as a strategy for compound selection in the drug discovery pipeline for Leishmaniasis. ACS Chem. Ashok, P. Berman, H. The protein data bank. Nucleic Acids Res. Bhagat, S. MedChemComm 5, — Brindisi, M. Structure-based discovery of the first non-covalent inhibitors of Leishmania major tryparedoxin peroxidase by high throughput docking. Casgrain, P. Cysteine peptidase B regulates Leishmania mexicana virulence through the modulation of GP63 expression. PLoS Pathog. Chen, C. A novel integrated framework and improved methodology of computer-aided drug design.

Copeland, N. Leishmaniasis: treatment updates and clinical practice guidelines review. Cordeiro, A. Crystal structure of dihydroorotate dehydrogenase from Leishmania major. Biochimie 94, — Cramer, R. Comparative molecular field analysis CoMFA. Effect of shape on binding of steroids to carrier proteins. Novel steroid derivatives: synthesis, antileishmanial activity, mechanism of action, and in silico physicochemical and pharmacokinetics studies.

De Luca, L. Discovery of benzimidazole-based Leishmania mexicana cysteine protease CPB2. Drug Des. Dikhit, M. LeishMicrosatDB: open source database of repeat sequences detected in six fully sequenced Leishmania genomes. Database bau Methods in Molecular Biology , eds M. Gore and U. Google Scholar. Ferreira, L. Molecular docking and structure-based drug design strategies. Therefore, we recommend using several Chemoinformatics programs and experimental data to predict drug-like properties of NCEs. Such an approach may accelerate drug discovery. Impact and Challenges of Chemoinformatics in Drug Discovery.

N2 - The last decade has witnessed the integration of systems biology and Chemoinformatics datasets. AB - The last decade has witnessed the integration of systems biology and Chemoinformatics datasets. Subbayan Pochi. Abstract The last decade has witnessed the integration of systems biology and Chemoinformatics datasets. Fingerprint Drug Discovery.