Mem Inst Oswaldo Cruz, Rio de Janeiro, VOLUME 117 | 2022

Computational approaches towards the discovery and optimisation of cruzain inhibitors

Viviane Corrêa Santos, Rafaela Salgado Ferreira+

Universidade Federal de Minas Gerais, Instituto de Ciências Biológicas, Departamento de Bioquímica e Imunologia, Laboratório de Modelagem Molecular e Planejamento de Fármacos, Belo Horizonte, MG, Brasil

DOI: 10.1590/0074-02760210385
682 views 174 downloads

The need to develop safer and more efficacious drugs to treat Chagas disease has motivated the search for cruzain inhibitors. Cruzain is the recombinant, truncated version of cruzipain, a cysteine protease from Trypanosoma cruzi with important roles during the parasite life cycle. Several computational techniques have been applied to discover and optimise cruzain inhibitors, providing a molecular basis to guide this process. Here, we review some of the most recent computational studies that provided important information for the design of cruzain inhibitors. Moreover, we highlight the diversity of applications of in silico techniques and their impact.

01. da Silva EB, Pereira GAN, Ferreira RS. Trypanosomal cysteine peptidases: target validation and drug design strategies. In: Sylke M, Rachel C, Ovidiu R, Paul MS, editors. Comprehensive analysis of parasite biology: rrom metabolism to drug discovery. Weinheim, Germany: Wiley-VCH; 2016. p. 121-45.
02. Santos VC, Oliveira AER, Campos ACB, Reis-Cunha JL, Bartholomeu DC, Teixeira SMR, et al. The gene repertoire of the main cysteine protease of Trypanosoma cruzi, cruzipain, reveals four sub-types with distinct active sites. Sci Rep. 2021; 11(1): 18231.
03. Choe Y, Leonetti F, Greenbaum DC, Lecaille F, Bogyo M, Brömme D, et al. Substrate profiling of cysteine proteases using a combinatorial peptide library identifies functionally unique specificities. J Biol Chem. 2006; 281(18): 12824-32.
04. Nascimento IJS, de Aquino TM, da Silva-Júnior EF. Cruzain and rhodesain inhibitors: last decade of advances in seeking for new compounds against American and African trypanosomiases. Curr Top Med Chem. 2021; 21(21): 1871-99.
05. Silva LR, Guimarães AS, do Nascimento J, Nascimento IJS, da Silva EB, McKerrow JH, et al. Computer-aided design of 1,4-naphthoquinone-based inhibitors targeting cruzain and rhodesain cysteine proteases. Bioorg Med Chem. 2021; 41: 116213.
06. De Souza ML, Rezende Jr CO, Ferreira RS, Chávez RME, Ferreira LLG, Slafer BW, et al. Discovery of potent, reversible, and competitive cruzain inhibitors with trypanocidal activity: a structure-based drug design approach. J Chem Inf Model. 2020; 60(2): 1028-41.
07. Ferreira RAA, Pauli I, Sampaio TS, de Souza ML, Ferreira LLG, Magalhães LG, et al. Structure-based and molecular modeling studies for the discovery of cyclic imides as reversible cruzain inhibitors with potent anti-Trypanosoma cruzi activity. Front Chem. 2019; 7: 798.
08. Barbosa da Silva E, Rocha DA, Fortes IS, Yang W, Monti L, Siqueira- Neto JL, et al. Structure-based optimization of quinazolines as cruzain and Tbr CATL inhibitors. J Med Chem. 2021; 64(17): 13054-71.
09. Pereira GAN, da Silva EB, Braga SFP, Leite PG, Martins LC, Vieira RP, et al. Discovery and characterization of trypanocidal cysteine protease inhibitors from the ‘malaria box.’ Eur J Med Chem. 2019; 179: 765-78.
10. Martins LC, Torres PHM, de Oliveira RB, Pascutti PG, Cino EA, Ferreira RS. Investigation of the binding mode of a novel cruzain inhibitor by docking, molecular dynamics, ab initio and MM/PBSA calculations. J Comput Aided Mol Des. 2018; 32(5): 591-605.
11. Santos LH, Waldner BJ, Fuchs JE, Pereira GAN, Liedl KR, Caffarena ER, et al. Understanding structure-activity relationships for trypanosomal cysteine protease inhibitors by simulations and free energy calculations. J Chem Inf Model. 2019; 59(1): 137-48.
12. Luchi AM, Villafañe RN, Gómez-Chávez JL, Bogado ML, Angelina EL, Peruchena NM. Combining charge density analysis with machine learning tools to investigate the cruzain inhibition mechanism. ACS Omega. 2019; 4(22): 19582-94.
13. Lameiro RF, Shamim A, Rosini F, Cendron R, Batista PHJ, Montanari CA. Synthesis, biochemical evaluation and molecular modeling studies of nonpeptidic nitrile-based fluorinated compounds. Future Med Chem. 2021; 13(1): 25-43.
14. Silva JRA, Cianni L, Araujo D, Batista PHJ, de Vita D, Rosini F, et al. Assessment of the cruzain cysteine protease reversible and irreversible covalent inhibition mechanism. J Chem Inf Model. 2020; 60(3): 1666-77.
15. Rosas-Jimenez JG, Garcia-Revilla MA, Madariaga-Mazon A, Martinez- Mayorga K. Predictive global models of cruzain inhibitors with large chemical coverage. ACS Omega. 2021; 6(10): 6722-35.
16. Álvarez LH, Gomes DEB, González JEH, Pascutti PG. Dissecting a novel allosteric mechanism of cruzain: a computer-aided approach. PLoS One. 2019; 14(1): e0211227.

Financial support: CAPES (Finance Code 001), FAPEMIG (Rede Mineira de Imunobiologicos - grant # REDE-00140-16), CNPq.
VCS holds a CAPES Postdoctoral fellowship (grant CAPES-EPIDEMIAS-0688/2020); RSF holds a CNPq researcher fellowship.
+ Corresponding author:
Received 08 December 2021
Accepted 05 January 2022

Our Location

Memórias do Instituto Oswaldo Cruz

Av. Brasil 4365, Castelo Mourisco 
sala 201, Manguinhos, 21040-900 
Rio de Janeiro, RJ, Brazil

Tel.: +55-21-2562-1222

This email address is being protected from spambots. You need JavaScript enabled to view it.

Support Program


faperj cnpq capes