Structure-Aided Computational Design of Triazole-Based Targeted Covalent Inhibitors of Cruzipain

Cruzipain (CZP), the major cysteine protease present in , the ethiological agent of Chagas disease, has attracted particular attention as a therapeutic target for the development of targeted covalent inhibitors (TCI). The vast chemical space associated with the enormous molecular diversity feasible...

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Bibliographic Details
Published in:	Molecules (Basel, Switzerland) Vol. 29; no. 17; p. 4224
Main Authors:	Cerutti, Juan Pablo, Diniz, Lucas Abreu, Santos, Viviane Corrêa, Vilchez Larrea, Salomé Catalina, Alonso, Guillermo Daniel, Ferreira, Rafaela Salgado, Dehaen, Wim, Quevedo, Mario Alfredo
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI AG 05-09-2024
Subjects:	Biological activity Chagas disease Chagas Disease - drug therapy Computer-Aided Design computer-aided drug design Cruzipain Cysteine Endopeptidases - chemistry Cysteine Proteinase Inhibitors - chemical synthesis Cysteine Proteinase Inhibitors - chemistry Cysteine Proteinase Inhibitors - pharmacology Design Drug Design Humans Ligands Molecular Docking Simulation Molecular Dynamics Simulation Molecular Structure Peptides Protozoa Protozoan Proteins - antagonists & inhibitors Protozoan Proteins - chemistry Structure-Activity Relationship targeted covalent inhibitors triazole derivatives Triazoles - chemical synthesis Triazoles - chemistry Triazoles - pharmacology Tropical diseases Trypanocidal Agents - chemical synthesis Trypanocidal Agents - chemistry Trypanocidal Agents - pharmacology Trypanosoma cruzi - drug effects Trypanosoma cruzi - enzymology Chagas disease Cruzipain targeted covalent inhibitors triazole derivatives computer-aided drug design
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Summary:	Cruzipain (CZP), the major cysteine protease present in , the ethiological agent of Chagas disease, has attracted particular attention as a therapeutic target for the development of targeted covalent inhibitors (TCI). The vast chemical space associated with the enormous molecular diversity feasible to explore by means of modern synthetic approaches allows the design of CZP inhibitors capable of exhibiting not only an efficient enzyme inhibition but also an adequate translation to anti- activity. In this work, a computer-aided design strategy was developed to combinatorially construct and screen large libraries of 1,4-disubstituted 1,2,3-triazole analogues, further identifying a selected set of candidates for advancement towards synthetic and biological activity evaluation stages. In this way, a virtual molecular library comprising more than 75 thousand diverse and synthetically feasible analogues was studied by means of molecular docking and molecular dynamic simulations in the search of potential TCI of CZP, guiding the synthetic efforts towards a subset of 48 candidates. These were synthesized by applying a Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) centered synthetic scheme, resulting in moderate to good yields and leading to the identification of 12 hits selectively inhibiting CZP activity with IC in the low micromolar range. Furthermore, four triazole derivatives showed good anti- inhibition when studied at 50 μM; and excelled for its high antitrypanocidal activity and low cytotoxicity, exhibiting complete in vitro biological activity translation from CZP to . Overall, not only merits further advancement to preclinical in vivo studies, but these findings also shed light on a valuable chemical space where molecular diversity might be explored in the search for efficient triazole-based antichagasic agents.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1420-3049 1420-3049
DOI:	10.3390/molecules29174224