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VIRTUAL SCREENING USING APPROVED DRUGS: IN SILICO EVALUATION OF ANTI HAT POTENTIALS

VIRTUAL SCREENING USING APPROVED DRUGS: IN SILICO EVALUATION OF ANTI HAT POTENTIALS

Raíssa Lima and Manuela Silva

Human African Trypanosomiasis (HAT), also called sleeping sickness, is a neglected disease caused by the parasite Trypanosoma brucei. The problem with HAT is that the drugs used in the treatment have several adverse effects (personality changes, psychosis and hyponatremia), negatively influencing therapeutic adherence. The objective of the work is to find potential substances that can act by inhibiting the 24-c-sterol-methytranferase (SMT) protein, which participates in the ergosterol biosynthesis, an important metabolic pathway for the parasite. First, the PDBid structures were prepared: 3BUS (a transferase of Lentzea aerocolonigenes, used in the prediction of the TbSMT model) and the SAH cofactor (S-Adenosyl-L-homocysteine). We used PDB2PQR web server for protonation of 3BUS (Amber force field) and OpenBabel was used for the ligand, both at pH 7.4. The addition of hydrogens, addition of Gasteiger charge and Grid formulation (center x: 15.278; y: 28.139; z: 30.662; and size x: 60; y: 60; z: 54;) was done using AutoDock Tools and Chimera . For redocking, the AutodDock Vina was used, testing 12 different exhaustiveness. The result that had the lowest RMSD (calculated with OpenBabel) was exhaustiveness 48, 1,355 Å. With the parameters validated, the docking was done between the TbSMT structure (obtained through previous work) and the shape of the cofactor before the action of the enzyme, SAM (S-Adenosyl-L-methionine). For this, SAM was removed from the PDBid: 4DF3 crystal (a transferase of Aeropyrum pernix). With the SMT structure containing the SAM cofactor, virtual screening was performed using a database present at ZINC, World. We found 10 promising substances classified by binding energy.