دورية أكاديمية
Molecular dynamics simulations of the free and inhibitor-bound cruzain systems in aqueous solvent: insights on the inhibition mechanism in acidic pH.
| العنوان: | Molecular dynamics simulations of the free and inhibitor-bound cruzain systems in aqueous solvent: insights on the inhibition mechanism in acidic pH. |
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| المؤلفون: | Hoelz LV; a Laboratório de Química Medicinal, Faculdade de Farmácia , Universidade Federal Fluminense (UFF) , Rua Mário Viana 523, Santa Rosa , Niterói , RJ 24241-000 , Brazil., Leal VF; a Laboratório de Química Medicinal, Faculdade de Farmácia , Universidade Federal Fluminense (UFF) , Rua Mário Viana 523, Santa Rosa , Niterói , RJ 24241-000 , Brazil., Rodrigues CR; b Laboratório ModMolQSAR, Faculdade de Farmácia , Universidade Federal do Rio de Janeiro (UFRJ) , Av. Carlos Chagas Filho 373, CCS, Rio de Janeiro , RJ 21941-599 , Brazil., Pascutti PG; c Laboratório de Modelagem e Dinâmica Molecular , Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro (UFRJ) , Av. Carlos Chagas Filho 373, CCS, Rio de Janeiro , RJ 21941-902 , Brazil., Albuquerque MG; d Laboratório de Modelagem Molecular , Instituto de Química, Universidade Federal do Rio de Janeiro (UFRJ) , Av. Athos da Silveira Ramos 149, CT, Rio de Janeiro , RJ 21949-900 , Brazil., Muri EM; a Laboratório de Química Medicinal, Faculdade de Farmácia , Universidade Federal Fluminense (UFF) , Rua Mário Viana 523, Santa Rosa , Niterói , RJ 24241-000 , Brazil., Dias LR; a Laboratório de Química Medicinal, Faculdade de Farmácia , Universidade Federal Fluminense (UFF) , Rua Mário Viana 523, Santa Rosa , Niterói , RJ 24241-000 , Brazil. |
| المصدر: | Journal of biomolecular structure & dynamics [J Biomol Struct Dyn] 2016 Sep; Vol. 34 (9), pp. 1969-78. Date of Electronic Publication: 2015 Nov 26. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Taylor & Francis Country of Publication: England NLM ID: 8404176 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1538-0254 (Electronic) Linking ISSN: 07391102 NLM ISO Abbreviation: J Biomol Struct Dyn Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: June 2012- : Oxon, UK : Taylor & Francis Original Publication: Guilderland, NY : Adenine Press, [c1983- |
| مواضيع طبية MeSH: | Molecular Dynamics Simulation*, Cysteine Endopeptidases/*chemistry , Cysteine Proteinase Inhibitors/*chemistry , Protozoan Proteins/*chemistry , Solvents/*chemistry , Trypanosoma cruzi/*enzymology, Binding Sites ; Catalytic Domain ; Cysteine Proteinase Inhibitors/pharmacology ; Hydrogen Bonding ; Hydrogen-Ion Concentration ; Models, Molecular ; Molecular Conformation ; Protein Interaction Domains and Motifs ; Protozoan Proteins/antagonists & inhibitors ; Structure-Activity Relationship |
| مستخلص: | The major cysteine protease of Trypanosoma cruzi, cruzain (CRZ), has been described as a therapeutic target for Chagas' disease, which affects millions of people worldwide. Thus, a series of CRZ inhibitors has been studied, including a new competitive inhibitor, Nequimed176 (NEQ176). Nevertheless, the structural and dynamic basis for CRZ inhibition remains unclear. Hoping to contribute to this ever-growing understanding of timescale dynamics in the CRZ inhibition mechanism, we have performed the first study using 100 ns of molecular dynamics (MD) simulations of two CRZ systems in an aqueous solvent under pH 5.5: CRZ in the apo form (ligand free) and CRZ complexed to NEQ176. According to the MD simulations, the enzyme adopts an open conformation in the apo form and a closed conformation in the NEQ176-CRZ complex. We also suggest that this closed conformation is related to the hydrogen-bonding interactions between NEQ176 and CRZ, which occurs through key residues, mainly Gly66, Met68, Asn69, and Leu160. In addition, the cross-correlation analysis shows evidence of the correlated motions among Ala110-Asp140, Leu160-Gly189, and Glu190-Gly215 subdomains, as well as, the movements related to Ala1-Thr59 and Asp60-Pro90 regions seem to be crucial for CRZ activity. |
| فهرسة مساهمة: | Keywords: Chagas’ disease; Nequimed176; cruzain; cysteine protease inhibitors; molecular dynamics simulation |
| المشرفين على المادة: | 0 (Cysteine Proteinase Inhibitors) 0 (Protozoan Proteins) 0 (Solvents) EC 3.4.22.- (Cysteine Endopeptidases) |
| تواريخ الأحداث: | Date Created: 20150929 Date Completed: 20170224 Latest Revision: 20170817 |
| رمز التحديث: | 20231215 |
| DOI: | 10.1080/07391102.2015.1100139 |
| PMID: | 26414241 |
| قاعدة البيانات: | MEDLINE |
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Full Text Finder | تدمد: | 1538-0254 |
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| DOI: | 10.1080/07391102.2015.1100139 |