Novel inhibitors of Trypanosoma cruzi dihydrofolate reductase

Zuccotto, Fabio; Zvelebil, Marketa; Brun, Reto; Chowdhury, Subrata; Lucrezia, Raffaella Di; Leal, Isabel; Maes, Louis; Pérez, Luis; González-Pacanowska, Dolores; Gilbert, Ian H.

doi:10.1016/s0223-5234(01)01235-1

Cited by 67 publications

(32 citation statements)

References 29 publications

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“…Homology modeling* or sequence threading techniques may be used to generate models of protein structures [62][63][64] which, although not as good as experimentally determined structures, can be used as docking targets. [65][66][67][68][69][70] Several studies have highlighted the importance of the conformation of a protein receptor for docking analysis. 68,71,72 McGovern and Shoichet 68 analyzed the influence of the receptor conformation on the final outcome of a docking screening of 95,000 small molecules.…”

Section: A Receptor Conformationmentioning

confidence: 99%

Combining docking and molecular dynamic simulations in drug design

2006

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A rational approach is needed to maximize the chances of finding new drugs, and to exploit the opportunities of potential new drug targets emerging from genomic and proteomic initiatives, and from the large libraries of small compounds now readily available through combinatorial chemistry. Despite a shaky early history, computer-aided drug design techniques can now be effective in reducing costs and speeding up drug discovery. This happy outcome results from development of more accurate and reliable algorithms, use of more thoughtfully planned strategies to apply them, and greatly increased computer power to allow studies with the necessary reliability to be performed. Our review focuses on applications and protocols, with the main emphasis on critical analysis of recent studies where docking calculations and molecular dynamics (MD) simulations were combined to dock small molecules into protein receptors. We highlight successes to demonstrate what is possible now, but also point out drawbacks and future directions. The review is structured to lead the reader from the simpler to more compute-intensive methods. Thus, while inexpensive and fast docking algorithms can be used to scan large compound libraries and reduce their size, more accurate but expensive MD simulations can be applied when a few selected ligand candidates remain. MD simulations can be used: during the preparation of the protein receptor before docking, to optimize its structure and account for protein flexibility; for the refinement of docked complexes, to include solvent effects and account for induced fit; to calculate binding free energies, to provide an accurate ranking of the potential ligands; and in the latest developments, during the docking process itself to find the binding site and correctly dock the ligand a priori.

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Section: A Receptor Conformationmentioning

confidence: 99%

Combining docking and molecular dynamic simulations in drug design

2006

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“…major and Le. mexicana, as well as T. brucei and T. cruzi (22)(23)(24)(25)(26)(27)(28)(29)(30). It was considered interesting to evaluate the activity of the rDHFR-TS in the presence of classical antifolates.…”

Section: Discussionmentioning

confidence: 99%

Caracterización bioquímica de la enzima bifuncional dihidrofolato reductasa-timidilato sintasa de Leishmania (Viannia) y su evaluación como blanco molecular

et al. 2013

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“…and trypanosomes (43). However, limited efforts have been devoted to investigating the effects of antifolates on T. cruzi infection (6,42,44). Results of these efforts suggested that some antifolates can inhibit the parasite but that they required relatively high doses.…”

Section: Discussionmentioning

confidence: 99%