Molecular modeling approach to predict a binding mode for the complex methotrexate-carboxypeptidase G2
| Autor: | Daniela Gonçales Rando, Kerly Fernanda Mesquita Pasqualoto, Elizabeth Igne Ferreira, Kely Medeiros Turra |
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| Rok vydání: | 2011 |
| Předmět: |
Molecular model
Stereochemistry Protein Conformation Antineoplastic Agents Molecular Dynamics Simulation Catalysis Inorganic Chemistry Residue (chemistry) Molecular recognition Glutamates Carboxypeptidase-G2 Moiety Humans Physical and Theoretical Chemistry Binding Sites biology Chemistry Hydrolysis Organic Chemistry MODELAGEM MOLECULAR Temperature Active site Water gamma-Glutamyl Hydrolase Prodrug Computer Science Applications Carboxypeptidase G Methotrexate Computational Theory and Mathematics Biochemistry biology.protein Thermodynamics Protein Binding |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| ISSN: | 0948-5023 |
| Popis: | Carboxypeptidase G(2) (CPG(2)) is a zinc-metalloenzyme employed in a range of cancer chemotherapy strategies by activating selectively nontoxic prodrugs into cytotoxic drugs in tumor as well as in the treatment of intoxication caused by high-doses of the anticancer drug methotrexate (MTX). CPG(2) catalyzes the hydrolytic cleavage of C-terminal of glutamate moiety from folic acid and analogues. Regardless of its extensive application, its mechanism of catalysis has not yet been determined and, so far, no co-crystallized complex has been published. So, in this study, molecular docking and a short molecular dynamics (MD) simulation sampling scheme, as a function of temperature, were performed to investigate a possible binding mode for MTX, a recognized substrate of CPG(2). The findings suggested that MTX interacts possibly in quite specific points of the CPG(2) active site, which are probably responsible for the molecular recognition and cleavage procedures. The MTX substrate fits well in the catalytic site by accommodating the pteridine moiety in an adjacent pocket to the active site whereas a glutamate moiety is pointed toward the protein surface. Additionally, a glutamate residue can interact with a crystallization water molecule in the active site, supporting its activation as a nucleophilic group. |
| Databáze: | OpenAIRE |
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