Virtual screening of new antitrypanosome compounds from a library of benzene sulfonyl derivatives of heterocycles

MIANA, G.E.; QUEVEDO, M.A.; VERA, DM; MAZZIERI, M.R.

Rosario

Congreso; 4to Congreso Argentino de Bioinformática y Biología Computacional; 2013

Asociación Argentina de Bioinformática y Biología Computacional

Background information Virtual high-throughput screening (vHTS) constitutes a useful complementary tool to experimental high-throughput screening (eHTS) techniques in rational drug design. The search for new drugs to treat Chagas disease (caused by Trypanosoma cruzi, Tc) need urgent commitment by academic teams, which may benefit from vHTS and HTS combined capabilities since more than 30 biological targets involved in Tc life cycle have been reported. In our laboratory, a chemical library of drug-like benzenesulfonylderivatives of heterocycles (BSHet) were designed as anti-TC drugs. Considering that eHTS against Tc of 109 BSHet identified 6 hits[1,2], and in order to gain insight into their mechanism of action, in this work we studied their interaction with 7 Tc key molecular targets with the aim of identifing the most probably enzyme targets. Exhaustive rigid-docking techniques as implemented in Open Eye Scientific Software (OESS) was used. Material and methods OESS was used to generate the chemical libraries The protocol started with the obtention of the crystal structures of selected Tc targets (PDB Code): Transsialidase (1MS9), Trypanothione Reductase (1BZL), Cysteine Protease (2OZ2), Phosphodiesterase C (3V94), Glyceraldehyde 3-phosphate Dehydrogenase (1K3T), Triosephosphate Isomerase (1SUX), Farnesyl Pyrophosphate Synthase (1YHL). Ten reference inhibitors with reported micromolar activity constituted the training dataset for validation. Ionization state and tautomer analyses were performed using MSketch®, after which Omega® [3] was applied to generate conformer libraries. Compounds were docked in the active site of the corresponding targets using FRED® [4]. After docking protocols were validated, a chemical library of BSHet (32 new ones and 6 hits) was generated and submitted to molecular docking against the 7 above-mentioned targets. Assayed BSHet compounds were synthesized in our laboratory. Results Good correlations between docked rank and reported antiparasitic potency were obtained for the training set used in the validation of the 7 targets. Outliers (false positive), could be attributed to different chemical substitution pattern and different assays of biological activity. The vHTS showed that only Transsialidase, Trypanothione reductase and Cysteine Protease would be appropriated molecular targets for analogs of the BSHet library. Some of them exhibited rankings, higher than reference compounds. Conclusions The OESS demonstrated to be useful for fast v-HTS when several possible targets has to be identified and it could be assumed as time and cost-saving tool for anti-Tc rational drug development.