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Discovery of Potent and Selective Leads against Toxoplasma gondii Dihydrofolate Reductase via Structure-Based Design.

Welsch ME, Zhou J, Gao Y, Yan Y, Porter G, Agnihotri G, Li Y, Lu H, Chen Z, Thomas SB
ACS Med Chem Lett 7 1124-1129 (2016)
Cited: 11 times
EuropePMC logo PMID: 27994750

Abstract

Current treatment of toxoplasmosis targets the parasite's folate metabolism through inhibition of dihydrofolate reductase (DHFR). The most widely used DHFR antagonist, pyrimethamine, was introduced over 60 years ago and is associated with toxicity that can be largely attributed to a similar affinity for parasite and human DHFR. Computational analysis of biochemical differences between Toxoplasma gondii and human DHFR enabled the design of inhibitors with both improved potency and selectivity. The approach described herein yielded TRC-19, a promising lead with an IC50 of 9 nM and 89-fold selectivity in favor of Toxoplasma gondii DHFR, as well as crystallographic data to substantiate in silico methodology. Overall, 50% of synthesized in silico designs met hit threshold criteria of IC50 < 10 μM and >2-fold selectivity favoring Toxoplasma gondii, further demonstrating the efficiency of our structure-based drug design approach.

Articles - 5t0l mentioned but not cited (1)

  1. Discovery of Potent and Selective Leads against Toxoplasma gondii Dihydrofolate Reductase via Structure-Based Design. Welsch ME, Zhou J, Gao Y, Yan Y, Porter G, Agnihotri G, Li Y, Lu H, Chen Z, Thomas SB. ACS Med Chem Lett 7 1124-1129 (2016)


Reviews citing this publication (6)

  1. A Systematic Review of In vitro and In vivo Activities of Anti-Toxoplasma Drugs and Compounds (2006-2016). Montazeri M, Sharif M, Sarvi S, Mehrzadi S, Ahmadpour E, Daryani A. Front Microbiol 8 25 (2017)
  2. Global initiative for congenital toxoplasmosis: an observational and international comparative clinical analysis. El Bissati K, Levigne P, Lykins J, Adlaoui EB, Barkat A, Berraho A, Laboudi M, El Mansouri B, Ibrahimi A, Rhajaoui M, Quinn F, Murugesan M, Seghrouchni F, Gómez-Marín JE, Peyron F, McLeod R. Emerg Microbes Infect 7 165 (2018)
  3. Trimethoprim and other nonclassical antifolates an excellent template for searching modifications of dihydrofolate reductase enzyme inhibitors. Wróbel A, Arciszewska K, Maliszewski D, Drozdowska D. J Antibiot (Tokyo) 73 5-27 (2020)
  4. Dihydrofolate reductase, thymidylate synthase, and serine hydroxy methyltransferase: successful targets against some infectious diseases. Shamshad H, Bakri R, Mirza AZ. Mol Biol Rep 49 6659-6691 (2022)
  5. Building Programs to Eradicate Toxoplasmosis Part I: Introduction and Overview. Felín MS, Wang K, Moreira A, Grose A, Leahy K, Zhou Y, Clouser FA, Siddiqui M, Leong N, Goodall P, Michalowski M, Ismail M, Christmas M, Schrantz S, Caballero Z, Norero X, Estripeaut D, Ellis D, Raggi C, Castro C, Moossazadeh D, Ramirez M, Pandey A, Ashi K, Dovgin S, Dixon A, Li X, Begeman I, Heichman S, Lykins J, Villalobos-Cerrud D, Fabrega L, Montalvo JLS, Mendivil C, Quijada MR, Fernández-Pirla S, de La Guardia V, Wong D, de Guevara ML, Flores C, Borace J, García A, Caballero N, Rengifo-Herrera C, de Saez MTM, Politis M, Wroblewski K, Karrison T, Ross S, Dogra M, Dhamsania V, Graves N, Kirchberg M, Mathur K, Aue A, Restrepo CM, Llanes A, Guzman G, Rebellon A, Boyer K, Heydemann P, Noble AG, Swisher C, Rabiah P, Withers S, Hull T, Su C, Blair M, Latkany P, Mui E, Vasconcelos-Santos DV, Villareal A, Perez A, Galvis CAN, Montes MV, Perez NIC, Ramirez M, Chittenden C, Wang E, Garcia-López LL, Muñoz-Ortiz J, Rivera-Valdivia N, Bohorquez-Granados MC, de-la-Torre GC, Padrieu G, Hernandez JDV, Celis-Giraldo D, Dávila JAA, Torres E, Oquendo MM, Arteaga-Rivera JY, Nicolae DL, Rzhetsky A, Roizen N, Stillwaggon E, Sawers L, Peyron F, Wallon M, Chapey E, Levigne P, Charter C, De Frias M, Montoya J, Press C, Ramirez R, Contopoulos-Ioannidis D, Maldonado Y, Liesenfeld O, Gomez C, Wheeler K, Holfels E, Frim D, McLone D, Penn R, Cohen W, Zehar S, McAuley J, Limonne D, Houze S, Abraham S, Piarroux R, Tesic V, Beavis K, Abeleda A, Sautter M, El Mansouri B, El Bachir A, Amarir F, El Bissati K, de-la-Torre A, Britton G, Motta J, Ortega-Barria E, Romero IL, Meier P, Grigg M, Gómez-Marín J, Kosagisharaf JR, Llorens XS, Reyes O, McLeod R. Curr Pediatr Rep 10 57-92 (2022)
  6. Building Programs to Eradicate Toxoplasmosis Part IV: Understanding and Development of Public Health Strategies and Advances "Take a Village". Felín MS, Wang K, Moreira A, Grose A, Leahy K, Zhou Y, Clouser FA, Siddiqui M, Leong N, Goodall P, Michalowski M, Ismail M, Christmas M, Schrantz S, Caballero Z, Norero X, Estripeaut D, Ellis D, Raggi C, Castro C, Moossazadeh D, Ramirez M, Pandey A, Ashi K, Dovgin S, Dixon A, Li X, Begeman I, Heichman S, Lykins J, Villalobos-Cerrud D, Fabrega L, Montalvo JLS, Mendivil C, Quijada MR, Fernández-Pirla S, de La Guardia V, Wong D, de Guevara ML, Flores C, Borace J, García A, Caballero N, Rengifo-Herrera C, de Saez MTM, Politis M, Ross S, Dogra M, Dhamsania V, Graves N, Kirchberg M, Mathur K, Aue A, Restrepo CM, Llanes A, Guzman G, Rebellon A, Boyer K, Heydemann P, Noble AG, Swisher C, Rabiah P, Withers S, Hull T, Frim D, McLone D, Su C, Blair M, Latkany P, Mui E, Vasconcelos-Santos DV, Villareal A, Perez A, Galvis CAN, Montes MV, Perez NIC, Ramirez M, Chittenden C, Wang E, Garcia-López LL, Padrieu G, Muñoz-Ortiz J, Rivera-Valdivia N, Bohorquez-Granados MC, de-la-Torre GC, Hernandez JDV, Celis-Giraldo D, Dávila JAA, Torres E, Oquendo MM, Arteaga-Rivera JY, Nicolae DL, Rzhetsky A, Roizen N, Stillwaggon E, Sawers L, Peyron F, Wallon M, Chapey E, Levigne P, Charter C, De Frias M, Montoya J, Press C, Ramirez R, Contopoulos-Ioannidis D, Maldonado Y, Liesenfeld O, Gomez C, Wheeler K, Zehar S, McAuley J, Limonne D, Houze S, Abraham S, Piarroux R, Tesic V, Beavis K, Abeleda A, Sautter M, El Mansouri B, El Bachir A, Amarir F, El Bissati K, Holfels E, Frim D, McLone D, Penn R, Cohen W, de-la-Torre A, Britton G, Motta J, Ortega-Barria E, Romero IL, Meier P, Grigg M, Gómez-Marín J, Kosagisharaf JR, Llorens XS, Reyes O, McLeod R. Curr Pediatr Rep 10 125-154 (2022)

Articles citing this publication (4)

  1. Discovery of Selective Toxoplasma gondii Dihydrofolate Reductase Inhibitors for the Treatment of Toxoplasmosis. Hopper AT, Brockman A, Wise A, Gould J, Barks J, Radke JB, Sibley LD, Zou Y, Thomas S. J Med Chem 62 1562-1576 (2019)
  2. QSAR Modeling for Multi-Target Drug Discovery: Designing Simultaneous Inhibitors of Proteins in Diverse Pathogenic Parasites. Kleandrova VV, Scotti L, Bezerra Mendonça Junior FJ, Muratov E, Scotti MT, Speck-Planche A. Front Chem 9 634663 (2021)
  3. Dual-Stage Picolinic Acid-Derived Inhibitors of Toxoplasma gondii. Khalifa MM, Martorelli Di Genova B, McAlpine SG, Gallego-Lopez GM, Stevenson DM, Rozema SD, Monaghan NP, Morris JC, Knoll LJ, Golden JE. ACS Med Chem Lett 11 2382-2388 (2020)
  4. Proteochemometric modeling of the origin of thymidylate synthase inhibition. Rasti B, Shahangian SS. Chem Biol Drug Des 91 1007-1016 (2018)


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