Studies of NMR, molecular docking, and molecular dynamics simulation of new promising inhibitors of cruzaine from the parasite Trypanosoma cruzi
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Cruzaine is the major cysteine protease of Trypanosoma cruzi. Cruzaine is involved throughout the parasite’s life cycle in host cells, and is a promising target in the search for new antichagasic agents. Quantum chemical calculations based on density functional theory (DFT B3LYP/cc-pVDZ) were performed to obtain nuclear magnetic resonance data and to optimize the geometry of four dihydrochalcones. The results showed good agreement with the experimental data and were used to suggest the relative stereochemistry of one of the four dihydrochalcones studied. In addition, we evaluated the interaction of cruzaine with these new inhibitors. We used molecular dynamics simulations, free energy calculations, and a per-residue energy decomposition method. It was observed that these molecules are capable of interacting with residues important for enzymatic activity, like Cys25, His161, and Asp160. The ranking of the inhibitors obtained from the binding free energy calculations is in agreement with that experimentally reported. The evaluation of the energy components involved in these calculations demonstrated that the van der Waals term is the major contributor to the drug–receptor stabilizing interactions.
KeywordsRMN New inhibitors Cruzaine Docking Molecular dynamics
Jorddy N. Cruz appreciate the support of the Federal University of Pará and the National Council for Scientific and Technological Development (CNPq). Conflict of interest The authors declare that there is no conflict of interest regarding the publication of this paper.
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Conflict of interest
The authors declare that they have no conflict of interest.
- Dennington R, Keith TA, Millam JM (2015) GaussView Version 5 Semichem Inc., Shawnee Mission, KS.Google Scholar
- Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery JA, Peralta JE, Ogliaro F, Bearpark M, Heyd JJ, Brothers E, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell A, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam JM, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ (2009) Gaussian 09, Revision B.01. Gaussian, Inc., Wallingford, CTGoogle Scholar
- Kollman PA, Massova I, Reyes C, Kuhn B, Huo S, Chong L, Lee M, Lee T, Duan Y, Wang W, Donini O, Cieplak P, Srinivasan J, Case DA, Cheatham TE (2000) Calculating structures and free energies of complex molecules: combining molecular mechanics and continuum models. Acc Chem Res 33:889–97CrossRefGoogle Scholar
- Magalhaes Moreira DR, de Oliveira ADT, Teixeira de Moraes Gomes PA, de Simone CA, Villela FS, Ferreira RS, da Silva AC, dos Santos TAR, Brelaz de Castro MCA, Pereira VRA, Leite ACL (2014) Conformational restriction of aryl thiosemicarbazones produces potent and selective anti-Trypanosoma cruzi compounds which induce apoptotic parasite death. Eur J Med Chem 75:467–478CrossRefGoogle Scholar
- Massarico Serafim RA, Gonçalves JE, de Souza FP, de Melo Loureiro AP, Storpirtis S, Krogh R, Andricopulo AD, Dias LC, Ferreira EI (2014) Design, synthesis and biological evaluation of hybrid bioisoster derivatives of N-acylhydrazone and furoxan groups with potential and selective anti-Trypanosoma cruzi activity. Eur J Med Chem 82:418–425CrossRefGoogle Scholar
- Moreira RYO, Brasil DSB, Alves CN, Guilhon GMSP, Santos LS, Arruda MSP, Müller AH, Barbosa PS, Abreu AS, Silva EO, Rumjanek VM, Souza J, da Silva ABF, Santos RH, de A (2008) Crystal structure and theoretical calculations of Julocrotine, a natural product with antileishmanial activity. Int J Quantum Chem 108:513–520CrossRefGoogle Scholar
- Morillo CA, Marin-Neto JA, Avezum A, Sosa-Estani S, Rassi A, Rosas F, Villena E, Quiroz R, Bonilla R, Britto C, Guhl F, Velazquez E, Bonilla L, Meeks B, Rao-Melacini P, Pogue J, Mattos A, Lazdins J, Rassi A, Connolly SJ, Yusuf S (2015) Randomized trial of benznidazole for chronic chagas’ cardiomyopathy. N Engl J Med 373:1295–1306CrossRefGoogle Scholar
- Wiggers HJ, Rocha JR, Fernandes WB, Sesti-Costa R, Carneiro ZA, Cheleski J, da Silva ABF, Juliano L, Cezari MHS, Silva JS, McKerrow JH, Montanari CA (2013) Non-peptidic cruzain inhibitors with trypanocidal activity discovered by virtual screening and in vitro assay. PLoS Negl Trop Dis 7:e2370CrossRefGoogle Scholar