Virtual screening: exploration of large databases aimed to the discovery of new anticonvulsant agents for the treatment of refractory epilepsy

MAURICIO E. DI IANNI; PABLO H. PALESTRO; ANDREA V. ENRIQUE; LUCIANA GAVERNET; ALAN TALEVI; LUIS BRUNO BLANCH

Rosario

Congreso; 4to. Congreso Argentino de Bioinformática y Biología Computacional (4CAB2C) y 4ta. Conferencia Internacional de la Sociedad Iberoamericana de Bioinformática (SolBio); 2013

Sociedad Iberoamericana de Bioinformática

Background P-glycoprotein (P-gp) is an ATP-dependent efflux transporter associated with multidrug resistance in several diseases such as cancer, epilepsy and AIDS. It is preferentially expressed in organs and tissues that function as a barrier (e.g. the gut walls or the blood?brain barrier) or promote the elimination of xenobiotics from the organism (e.g. liver and kidney) [1]. P-gp limits drug bioavailability; thus, the recognition of Pgp substrates at the early stages of the drug development cycle is essential for the development of new chemotherapeutic agents to deal with multidrug resistance issues. Materials and methods We have applied a 3-model ensemble of 2D classifiers capable of differentiating P-gp substrates from non substrates [2] jointly with a previously reported topological model capable of identifying anticonvulsants in the Maximal Electroshock Seizure (MES) [3] test to ZINC 5 and DrugBank databases [4,5] in order to find possible candidates for the treatment of P-gp mediated refractory epilepsy. The resulting candidates were docked into the 3D structure of human Pgp, obtained from an homology model based on the crystal structure of mouse P-gp (pdb code: 3G60). Results From the database compounds chosen as candidates, a subset of 380 molecules was selected for the docking stage. After the analysis, 12 structurally diverse compounds were acquired and tested in animal models of seizure. All 12 candidates showed some level of protection against MES test. Conclusion Early recognition of substrates of efflux transporters is a key step in drug development projects in order to avoid transporter-mediated multidrug resistance issues, especially when the drug under development is aimed at the treatment of health conditions with high prevalence of drug resistance (e.g., epilepsy).