title: Combining molecular docking and QSAR studies for modelling the antigyrase activity of cyclothialidine derivatives.
abstract: DNA gyrase is a well-established antibacterial target consisting of two subunits, GyrA and GyrB, in a heterodimer A(2)B(2), where GyrB catalyzes the hydrolysis of ATP. Cyclothialidine (Ro 09-1437) has been considered as a promising inhibitor whose modifications might lead to more potent compounds against the enzyme. We report here for the first time, QSAR studies regarding to ATPase inhibitors of DNA Gyrase. 1D, 2D and 3D descriptors from DRAGON software were used on a set of 42 cyclothialidine derivatives. Based on the core of the cyclothialidine GR122222X, different conformations were created by using OMEGA. FRED was used to dock these conformers in the cavity of the GyrB subunit to select the best conformations, paying special attention to the 12-membered ring. Three QSAR models were developed considering the dimension of the descriptors. The models were robust, predictive and good in statistical significance, over 70% of the experimental variance was explained. Interpretability of the models was possible by extracting the SAR(s) encoded by these predictive models. Analyzing the compound-enzyme interactions of the complexes obtained by docking allowed us to increase the reliability of the information obtained for the QSAR models.
authors.affiliation: Centro de Bioactivos Quimicos, Universidad Central "Marta Abreu" de las Villas, Carretera a Camajuani Km 5.5, Santa Clara (54830), Villa Clara, Cuba. liane.saiz@gmail.com
authors.forename: Liane
authors.initials: L
authors.lastname: Saíz-Urra
authors.forename: Miguel Ángel
authors.initials: MÁ
authors.lastname: Cabrera Pérez
authors.forename: Aliuska Morales
authors.initials: AM
authors.lastname: Helguera
authors.forename: Matheus
authors.initials: M
authors.lastname: Froeyen
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry; D000900:Anti-Bacterial Agents / Q000737:chemistry*; D001419:Bacteria / Q000737:chemistry / Q000201:enzymology; D001665:Binding Sites; D027081:DNA Gyrase / Q000737:chemistry*; D015195:Drug Design; D062105:Molecular Docking Simulation; D010456:Peptides, Cyclic / Q000737:chemistry*; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D013816:Thermodynamics; D059005:Topoisomerase II Inhibitors / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D010456:Peptides, Cyclic; D059005:Topoisomerase II Inhibitors; C085889:cyclothialidine; C088717:GR 122222X; D000255:Adenosine Triphosphate; D027081:DNA Gyrase