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Non-peptidic cruzain inhibitors with trypanocidal activity discovered by virtual screening and in vitro assay
A multi-step cascade strategy using integrated ligand- and target-based virtual screening methods was developed to select a small number of compounds from the ZINC database to be evaluated for trypanocidal activity. Winnowing the database to 23 selected compounds, 12 non-covalent binding cruzain inh...
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| Published in: | PLoS neglected tropical diseases 2013-08, Vol.7 (8), p.e2370 |
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| creator | Wiggers, Helton J Rocha, Josmar R Fernandes, William B Sesti-Costa, Renata Carneiro, Zumira A Cheleski, Juliana da Silva, Albérico B F Juliano, Luiz Cezari, Maria H S Silva, João S McKerrow, James H Montanari, Carlos A |
| description | A multi-step cascade strategy using integrated ligand- and target-based virtual screening methods was developed to select a small number of compounds from the ZINC database to be evaluated for trypanocidal activity. Winnowing the database to 23 selected compounds, 12 non-covalent binding cruzain inhibitors with affinity values (K i) in the low micromolar range (3-60 µM) acting through a competitive inhibition mechanism were identified. This mechanism has been confirmed by determining the binding mode of the cruzain inhibitor Nequimed176 through X-ray crystallographic studies. Cruzain, a validated therapeutic target for new chemotherapy for Chagas disease, also shares high similarity with the mammalian homolog cathepsin L. Because increased activity of cathepsin L is related to invasive properties and has been linked to metastatic cancer cells, cruzain inhibitors from the same library were assayed against it. Affinity values were in a similar range (4-80 µM), yielding poor selectivity towards cruzain but raising the possibility of investigating such inhibitors for their effect on cell proliferation. In order to select the most promising enzyme inhibitors retaining trypanocidal activity for structure-activity relationship (SAR) studies, the most potent cruzain inhibitors were assayed against T. cruzi-infected cells. Two compounds were found to have trypanocidal activity. Using compound Nequimed42 as precursor, an SAR was established in which the 2-acetamidothiophene-3-carboxamide group was identified as essential for enzyme and parasite inhibition activities. The IC50 value for compound Nequimed42 acting against the trypomastigote form of the Tulahuen lacZ strain was found to be 10.6±0.1 µM, tenfold lower than that obtained for benznidazole, which was taken as positive control. In addition, by employing the strategy of molecular simplification, a smaller compound derived from Nequimed42 with a ligand efficiency (LE) of 0.33 kcal mol(-1) atom(-1) (compound Nequimed176) is highlighted as a novel non-peptidic, non-covalent cruzain inhibitor as a trypanocidal agent candidate for optimization. |
| doi_str_mv | 10.1371/journal.pntd.0002370 |
| format | article |
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Winnowing the database to 23 selected compounds, 12 non-covalent binding cruzain inhibitors with affinity values (K i) in the low micromolar range (3-60 µM) acting through a competitive inhibition mechanism were identified. This mechanism has been confirmed by determining the binding mode of the cruzain inhibitor Nequimed176 through X-ray crystallographic studies. Cruzain, a validated therapeutic target for new chemotherapy for Chagas disease, also shares high similarity with the mammalian homolog cathepsin L. Because increased activity of cathepsin L is related to invasive properties and has been linked to metastatic cancer cells, cruzain inhibitors from the same library were assayed against it. Affinity values were in a similar range (4-80 µM), yielding poor selectivity towards cruzain but raising the possibility of investigating such inhibitors for their effect on cell proliferation. In order to select the most promising enzyme inhibitors retaining trypanocidal activity for structure-activity relationship (SAR) studies, the most potent cruzain inhibitors were assayed against T. cruzi-infected cells. Two compounds were found to have trypanocidal activity. Using compound Nequimed42 as precursor, an SAR was established in which the 2-acetamidothiophene-3-carboxamide group was identified as essential for enzyme and parasite inhibition activities. The IC50 value for compound Nequimed42 acting against the trypomastigote form of the Tulahuen lacZ strain was found to be 10.6±0.1 µM, tenfold lower than that obtained for benznidazole, which was taken as positive control. In addition, by employing the strategy of molecular simplification, a smaller compound derived from Nequimed42 with a ligand efficiency (LE) of 0.33 kcal mol(-1) atom(-1) (compound Nequimed176) is highlighted as a novel non-peptidic, non-covalent cruzain inhibitor as a trypanocidal agent candidate for optimization.</description><identifier>ISSN: 1935-2735</identifier><identifier>ISSN: 1935-2727</identifier><identifier>EISSN: 1935-2735</identifier><identifier>DOI: 10.1371/journal.pntd.0002370</identifier><identifier>PMID: 23991231</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Anti-infective agents ; Antiprotozoal Agents - isolation & purification ; Antiprotozoal Agents - pharmacology ; Biology ; Chemistry ; Chemotherapy ; Crystallography ; Crystallography, X-Ray ; Cysteine Endopeptidases - chemistry ; Cysteine Endopeptidases - metabolism ; Drug Evaluation, Preclinical - methods ; Drugs ; Enzymes ; Inhibitory Concentration 50 ; Kinetics ; Ligands ; Mammals ; Methods ; Microbial sensitivity tests ; Parasites ; Parasitic Sensitivity Tests - methods ; Physics ; Physiological aspects ; Poverty ; Protein Binding ; Protein Conformation ; Protozoan Proteins - antagonists & inhibitors ; Protozoan Proteins - chemistry ; Protozoan Proteins - metabolism ; Structure-Activity Relationship ; Structure-activity relationship (Pharmacology) ; Structure-activity relationships ; Testing ; Trypanosoma cruzi ; Trypanosoma cruzi - drug effects ; Trypanosoma cruzi - enzymology</subject><ispartof>PLoS neglected tropical diseases, 2013-08, Vol.7 (8), p.e2370</ispartof><rights>COPYRIGHT 2013 Public Library of Science</rights><rights>2013 Wiggers et al 2013 Wiggers et al</rights><rights>2013 Wiggers et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited: Wiggers HJ, Rocha JR, Fernandes WB, Sesti-Costa R, Carneiro ZA, et al. (2013) Non-peptidic Cruzain Inhibitors with Trypanocidal Activity Discovered by Virtual Screening and In Vitro Assay. 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Winnowing the database to 23 selected compounds, 12 non-covalent binding cruzain inhibitors with affinity values (K i) in the low micromolar range (3-60 µM) acting through a competitive inhibition mechanism were identified. This mechanism has been confirmed by determining the binding mode of the cruzain inhibitor Nequimed176 through X-ray crystallographic studies. Cruzain, a validated therapeutic target for new chemotherapy for Chagas disease, also shares high similarity with the mammalian homolog cathepsin L. Because increased activity of cathepsin L is related to invasive properties and has been linked to metastatic cancer cells, cruzain inhibitors from the same library were assayed against it. Affinity values were in a similar range (4-80 µM), yielding poor selectivity towards cruzain but raising the possibility of investigating such inhibitors for their effect on cell proliferation. In order to select the most promising enzyme inhibitors retaining trypanocidal activity for structure-activity relationship (SAR) studies, the most potent cruzain inhibitors were assayed against T. cruzi-infected cells. Two compounds were found to have trypanocidal activity. Using compound Nequimed42 as precursor, an SAR was established in which the 2-acetamidothiophene-3-carboxamide group was identified as essential for enzyme and parasite inhibition activities. The IC50 value for compound Nequimed42 acting against the trypomastigote form of the Tulahuen lacZ strain was found to be 10.6±0.1 µM, tenfold lower than that obtained for benznidazole, which was taken as positive control. In addition, by employing the strategy of molecular simplification, a smaller compound derived from Nequimed42 with a ligand efficiency (LE) of 0.33 kcal mol(-1) atom(-1) (compound Nequimed176) is highlighted as a novel non-peptidic, non-covalent cruzain inhibitor as a trypanocidal agent candidate for optimization.</description><subject>Anti-infective agents</subject><subject>Antiprotozoal Agents - isolation & purification</subject><subject>Antiprotozoal Agents - pharmacology</subject><subject>Biology</subject><subject>Chemistry</subject><subject>Chemotherapy</subject><subject>Crystallography</subject><subject>Crystallography, X-Ray</subject><subject>Cysteine Endopeptidases - chemistry</subject><subject>Cysteine Endopeptidases - metabolism</subject><subject>Drug Evaluation, Preclinical - methods</subject><subject>Drugs</subject><subject>Enzymes</subject><subject>Inhibitory Concentration 50</subject><subject>Kinetics</subject><subject>Ligands</subject><subject>Mammals</subject><subject>Methods</subject><subject>Microbial sensitivity tests</subject><subject>Parasites</subject><subject>Parasitic Sensitivity Tests - methods</subject><subject>Physics</subject><subject>Physiological aspects</subject><subject>Poverty</subject><subject>Protein Binding</subject><subject>Protein Conformation</subject><subject>Protozoan Proteins - antagonists & inhibitors</subject><subject>Protozoan Proteins - chemistry</subject><subject>Protozoan Proteins - metabolism</subject><subject>Structure-Activity Relationship</subject><subject>Structure-activity relationship (Pharmacology)</subject><subject>Structure-activity relationships</subject><subject>Testing</subject><subject>Trypanosoma cruzi</subject><subject>Trypanosoma cruzi - drug effects</subject><subject>Trypanosoma cruzi - enzymology</subject><issn>1935-2735</issn><issn>1935-2727</issn><issn>1935-2735</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>DOA</sourceid><recordid>eNptUk2L2zAQNaWlu037D0prKPTmVB-2FV0Ky9KPhaW9tGcxlsaxgiMZScni_voqTXZJoOggaea9N9LMK4q3lCwpF_TTxu-Cg3E5uWSWhBDGBXlWXFPJm4oJ3jw_O18Vr2LcENLIZkVfFleMS0kZp9fF9od31YRTssbqUofdH7CutG6wnU0-xPLBpqFMYZ7AeW0NjCXoZPc2zaWxUfs9BjRlN5d7G9Iup6MOiM66dQnOZKWcSMGXECPMr4sXPYwR35z2RfH765dft9-r-5_f7m5v7ivdyDZVQrC25Supa6RoJO1bbDhSIwRpO0pl067ytVsho6aVrOlAko5KTQzKHnTHF8X7o-40-qhOnYqK1pxJSVY1z4i7I8J42Kgp2C2EWXmw6l_Ah7WCkKweUfWUMSLbloI2NbQEWC0Yily0E32Hh2qfT9V23RaNRpcCjBeilxlnB7X2e8VFkwcns8CHo8Aacj3rep9hepvbq254XQtS13m8i2L5H1ReBrdWe4e9zfELwsczwoAwpiH6cZesd_ESWB-BOvgYA_ZPb6dEHcz22EJ1MJs6mS3T3p3_-4n06C7-FyRh1BA</recordid><startdate>20130801</startdate><enddate>20130801</enddate><creator>Wiggers, Helton J</creator><creator>Rocha, Josmar R</creator><creator>Fernandes, William B</creator><creator>Sesti-Costa, Renata</creator><creator>Carneiro, Zumira A</creator><creator>Cheleski, Juliana</creator><creator>da Silva, Albérico B F</creator><creator>Juliano, Luiz</creator><creator>Cezari, Maria H S</creator><creator>Silva, João S</creator><creator>McKerrow, James H</creator><creator>Montanari, Carlos A</creator><general>Public Library of Science</general><general>Public Library of Science (PLoS)</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>5PM</scope><scope>DOA</scope></search><sort><creationdate>20130801</creationdate><title>Non-peptidic cruzain inhibitors with trypanocidal activity discovered by virtual screening and in vitro assay</title><author>Wiggers, Helton J ; Rocha, Josmar R ; Fernandes, William B ; Sesti-Costa, Renata ; Carneiro, Zumira A ; Cheleski, Juliana ; da Silva, Albérico B F ; Juliano, Luiz ; Cezari, Maria H S ; Silva, João S ; McKerrow, James H ; Montanari, Carlos A</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c596t-77266389c4e1ed91f6e53e1d7706b1195683e1b8e21d6925ba90b19c0de9facb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Anti-infective agents</topic><topic>Antiprotozoal Agents - isolation & purification</topic><topic>Antiprotozoal Agents - pharmacology</topic><topic>Biology</topic><topic>Chemistry</topic><topic>Chemotherapy</topic><topic>Crystallography</topic><topic>Crystallography, X-Ray</topic><topic>Cysteine Endopeptidases - chemistry</topic><topic>Cysteine Endopeptidases - metabolism</topic><topic>Drug Evaluation, Preclinical - methods</topic><topic>Drugs</topic><topic>Enzymes</topic><topic>Inhibitory Concentration 50</topic><topic>Kinetics</topic><topic>Ligands</topic><topic>Mammals</topic><topic>Methods</topic><topic>Microbial sensitivity tests</topic><topic>Parasites</topic><topic>Parasitic Sensitivity Tests - methods</topic><topic>Physics</topic><topic>Physiological aspects</topic><topic>Poverty</topic><topic>Protein Binding</topic><topic>Protein Conformation</topic><topic>Protozoan Proteins - antagonists & inhibitors</topic><topic>Protozoan Proteins - chemistry</topic><topic>Protozoan Proteins - metabolism</topic><topic>Structure-Activity Relationship</topic><topic>Structure-activity relationship (Pharmacology)</topic><topic>Structure-activity relationships</topic><topic>Testing</topic><topic>Trypanosoma cruzi</topic><topic>Trypanosoma cruzi - drug effects</topic><topic>Trypanosoma cruzi - enzymology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Wiggers, Helton J</creatorcontrib><creatorcontrib>Rocha, Josmar R</creatorcontrib><creatorcontrib>Fernandes, William B</creatorcontrib><creatorcontrib>Sesti-Costa, Renata</creatorcontrib><creatorcontrib>Carneiro, Zumira A</creatorcontrib><creatorcontrib>Cheleski, Juliana</creatorcontrib><creatorcontrib>da Silva, Albérico B F</creatorcontrib><creatorcontrib>Juliano, Luiz</creatorcontrib><creatorcontrib>Cezari, Maria H S</creatorcontrib><creatorcontrib>Silva, João S</creatorcontrib><creatorcontrib>McKerrow, James H</creatorcontrib><creatorcontrib>Montanari, Carlos A</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PLoS neglected tropical diseases</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Wiggers, Helton J</au><au>Rocha, Josmar R</au><au>Fernandes, William B</au><au>Sesti-Costa, Renata</au><au>Carneiro, Zumira A</au><au>Cheleski, Juliana</au><au>da Silva, Albérico B F</au><au>Juliano, Luiz</au><au>Cezari, Maria H S</au><au>Silva, João S</au><au>McKerrow, James H</au><au>Montanari, Carlos A</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Non-peptidic cruzain inhibitors with trypanocidal activity discovered by virtual screening and in vitro assay</atitle><jtitle>PLoS neglected tropical diseases</jtitle><addtitle>PLoS Negl Trop Dis</addtitle><date>2013-08-01</date><risdate>2013</risdate><volume>7</volume><issue>8</issue><spage>e2370</spage><pages>e2370-</pages><issn>1935-2735</issn><issn>1935-2727</issn><eissn>1935-2735</eissn><notes>Conceived and designed the experiments: HJW JRR WBF JHM CAM. Performed the experiments: HJW JRR WBF RSC ZAC JC ABFdS LJ MHSC JSS. Analyzed the data: HJW JRR WBF JHM CAM. Contributed reagents/materials/analysis tools: ZAC JC MHSC. Wrote the paper: HJW JRR JHM CAM. Designed the cruzain construction: LJ MHSC. Designed the X-ray crystallographic study: WBF JHM.</notes><notes>The authors have declared that no competing interests exist.</notes><abstract>A multi-step cascade strategy using integrated ligand- and target-based virtual screening methods was developed to select a small number of compounds from the ZINC database to be evaluated for trypanocidal activity. Winnowing the database to 23 selected compounds, 12 non-covalent binding cruzain inhibitors with affinity values (K i) in the low micromolar range (3-60 µM) acting through a competitive inhibition mechanism were identified. This mechanism has been confirmed by determining the binding mode of the cruzain inhibitor Nequimed176 through X-ray crystallographic studies. Cruzain, a validated therapeutic target for new chemotherapy for Chagas disease, also shares high similarity with the mammalian homolog cathepsin L. Because increased activity of cathepsin L is related to invasive properties and has been linked to metastatic cancer cells, cruzain inhibitors from the same library were assayed against it. Affinity values were in a similar range (4-80 µM), yielding poor selectivity towards cruzain but raising the possibility of investigating such inhibitors for their effect on cell proliferation. In order to select the most promising enzyme inhibitors retaining trypanocidal activity for structure-activity relationship (SAR) studies, the most potent cruzain inhibitors were assayed against T. cruzi-infected cells. Two compounds were found to have trypanocidal activity. Using compound Nequimed42 as precursor, an SAR was established in which the 2-acetamidothiophene-3-carboxamide group was identified as essential for enzyme and parasite inhibition activities. The IC50 value for compound Nequimed42 acting against the trypomastigote form of the Tulahuen lacZ strain was found to be 10.6±0.1 µM, tenfold lower than that obtained for benznidazole, which was taken as positive control. In addition, by employing the strategy of molecular simplification, a smaller compound derived from Nequimed42 with a ligand efficiency (LE) of 0.33 kcal mol(-1) atom(-1) (compound Nequimed176) is highlighted as a novel non-peptidic, non-covalent cruzain inhibitor as a trypanocidal agent candidate for optimization.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>23991231</pmid><doi>10.1371/journal.pntd.0002370</doi><oa>free_for_read</oa></addata></record> |
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| identifier | ISSN: 1935-2735 |
| ispartof | PLoS neglected tropical diseases, 2013-08, Vol.7 (8), p.e2370 |
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| source | Open Access: PubMed Central; Publicly Available Content Database |
| subjects | Anti-infective agents Antiprotozoal Agents - isolation & purification Antiprotozoal Agents - pharmacology Biology Chemistry Chemotherapy Crystallography Crystallography, X-Ray Cysteine Endopeptidases - chemistry Cysteine Endopeptidases - metabolism Drug Evaluation, Preclinical - methods Drugs Enzymes Inhibitory Concentration 50 Kinetics Ligands Mammals Methods Microbial sensitivity tests Parasites Parasitic Sensitivity Tests - methods Physics Physiological aspects Poverty Protein Binding Protein Conformation Protozoan Proteins - antagonists & inhibitors Protozoan Proteins - chemistry Protozoan Proteins - metabolism Structure-Activity Relationship Structure-activity relationship (Pharmacology) Structure-activity relationships Testing Trypanosoma cruzi Trypanosoma cruzi - drug effects Trypanosoma cruzi - enzymology |
| title | Non-peptidic cruzain inhibitors with trypanocidal activity discovered by virtual screening and in vitro assay |
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