Combining molecular dynamics and docking simulations of the cytidine deaminase from Mycobacterium tuberculosis H37Rv.

Luís Fernando Saraiva Macedo Timmers, Rodrigo Gay Ducati, Zilpa Adriana Sánchez-Quitian, Luiz Augusto Basso, Diógenes Santiago Santos, Walter Filgueira de Azevedo

Faculdade de Biociências, Instituto Nacional de Ciência e Tecnologia em Tuberculose (INCT-TB), Laboratório de Bioquímica Estrutural (LaBioQuest), Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Av. Ipiranga 6681, Porto Alegre, RS 90619-900, Brazil.

Journal of molecular modeling 2012 Feb

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Cytidine Deaminase (CD) is an evolutionarily conserved enzyme that participates in the pyrimidine salvage pathway recycling cytidine and deoxycytidine into uridine and deoxyuridine, respectively. Here, our goal is to apply computational techniques in the pursuit of potential inhibitors of Mycobacterium tuberculosis CD (MtCDA) enzyme activity. Molecular docking simulation was applied to find the possible hit compounds. Molecular dynamics simulations were also carried out to investigate the physically relevant motions involved in the protein-ligand recognition process, aiming at providing estimates for free energy of binding. The proposed approach was capable of identifying a potential inhibitor, which was experimentally confirmed by IC(50) evaluation. Our findings open up the possibility to extend this protocol to different databases in order to find new potential inhibitors for promising targets based on a rational drug design process.

Citation

Luís Fernando Saraiva Macedo Timmers, Rodrigo Gay Ducati, Zilpa Adriana Sánchez-Quitian, Luiz Augusto Basso, Diógenes Santiago Santos, Walter Filgueira de Azevedo. Combining molecular dynamics and docking simulations of the cytidine deaminase from Mycobacterium tuberculosis H37Rv. Journal of molecular modeling. 2012 Feb;18(2):467-79