Virtual Analysis in Repurposing of Various Drug Classes as Antileishmanial Agents

Background and purpose: Drug repurposing or the study on the possible application of some drugs for treatment or control of other diseases, is an important and applied research domain. A major advantage of “drug repurposing” with regard to other drug discovery methods is that a nominated drug molecule with acceptable pharmacokinetics as a lead compound does not cause serious problems in optimizing toxicity and it may be focused on pharmacodynamics. According to the importance of the subject, a present contribution has been dedicated to the in-silico analysis of a few drug classes with the aim of achieving potential anti-leishmanial pharmacophores. Materials and methods: At first, diverse protein receptors within leishmania parasite were identified via surveying Brookhaven Protein Data Bank (PDB) and literature review (7 enzymes). Ligand database included 128 FDA approved drugs within different pharmacological classes. After validation of AutoDock 4.2 by re-docking of crystallographic ligands, ligand structures were docked into the binding sites of targets to rank the drugs on the basis of qualitative and quantitative analysis of drug-enzyme binding patterns. Top binded drugs were subjected to more delicate evaluations to offer hypothetical anti leishmanial pharmacophores. Results: Several results were obtained from the present study particularly as the structure-binding relationship view but just the most important once are presented here. Highest free binding energy was estimated for an antidiabetic drug Nateglinide (ΔGb =30/13-kcal/mol) in binding to farnesyl diphosphate synthase. Amomg steroids as the top ranked derivatives with regard to the number of interacting leishmanial enzymes, Norgestrol (ΔGb = -9/48 kcal/mol) and Testosterone (ΔGb = 05/8-kcal/mol) exhibited higher enzyme binding affinities to adenine phosphoribosyl transferase. Arg82 was found as a key residue in making hydrogen bonds to this enzyme. Results of the current study revealed that fused tricyclic structural pattern could also make desirable binding interactions with some leishmanial targets and in particular mitogen activated protein kinase (MAPK) and pteridine reductase 1 (PTR1). Conclusion: Results of molecular docking indicated that superior structure with regard to the binding affinity to leishmanial targets and in particular adenine phosphoribosyl transferase is a steroid. Incorporation of any rings to the steroid rings A or D (Danazol and spironolactone) caused decreased free binding energies which might be attributed to the steric hindrance of bulkier molecules. Among the drugs with fused tricyclic scaffold, enzyme binding could also be related to fusing pattern of the rings and as could be observed in the cases of Mirtazapine and Carbamazepine, besides fusing pattern, substitution of 6-membered side rings with smaller 5-membered ones (Alprazolam and Flumazenil) led to the decreased binding affinities. Purely hydrophobic binding interactions of Norgestrol in binding site of triosephosphate isomerase and PTR1, Testosterone in binding site of farnesyl diphosphate synthase and MAPK and Mirtazapine in binding site of deoxy uridine triphosphate emphasized on the potential of these drugs as primary structural patterns for designing enzyme antagonists. Regarding the obtained results for steroids and fused tricyclic scaffolds, it might be possible to think about anti-leishmanial molecules with multi-target inhibitory potentials