Discipline: Biological Sciences
Subcategory: Chemistry (not Biochemistry)
Charles O. Ogindo - Howard University
Co-Author(s): Oladapo Bakare, Yayin Fang, and William Southerland
American trypanosomiasis affect over 8 million people in the Americas. The current drugs offered by CDC, benznidazole and nifurtimox, are not effective unless treatment is started within two months of infection. Moreover, they are associated with serious side effects in over 40% of treated patients. We here present our preliminary results in the use of molecular modeling techniques to design novel safe and effective drugs for American trypanosomiasis, also known as Chagas disease.
In this quest we have created a 3D homology model of Trypanosoma cruzi (T. cruzi) tubulin dimer, located the binding pocket of imidonaphthoquinone derivatives whose T. cruzi tubulin polymerization inhibition IC50s were hitherto determined, and carried out receptor based pharmacophore modeling. Bos Taurus tubulin dimer PDB ID 1JFF was used as a template to model T. cruzi tubulin, using Amber 12EHT modules implemented in MOE. The probable binding pockets were located using SiteFind algorithm and were rated and docked with our small molecules. Ligand-receptor complex stabilization was determined using London dG forcefield, which incorporates enthalpy and entropy terms and rescored with GBVI/WSA dG forcefield that incorporates an extra term for solvation energy. The binding pocket was identified by comparison of the plot of the binding energies and ligand activities, wherein the pocket that exhibited a more accurate correlation between binding energies and assay ligand polymerization inhibition IC50s was designated as the putative pocket. This pocket, located at the intra-dimer region, was used for pharmacophore features elucidation and subsequent formulation of pharmacophore queries for ligand search and iterative optimization of lead compounds. Ligands with naphthoquinone motif were mined from ChEMBL, prepared, docked and filtered with pharmacophore query constraints to predict actives. We incorporated validated QSARs models integrated in the MOE as filters to give compounds with SlogP values between -4 and 8, those that were not reactive, not mutagenic, and those predicted to be synthetically reasonable. The compounds in our output file were sorted according to calculated Gibbs free energy of binding. In order to maximize the drugs’ potency against the parasite tubulin while protecting the host, a significant differential in the binding affinities of the drug for T. cruzi tubulin and human tubulin is necessary. This desirable quality was designed by (i) observing and exploiting the differences in size and geometry of the respective pockets (ii) using the pharmacophore features operative in the T. cruzi tubulin pocket to design ligands that are specially stabilized there, thereby increasing the odds that such a ligand will bind well in the human pocket, and (iv) by docking the designed ligands in the two pockets to ascertain that the binding energy favors T. cruzi pocket. Further refining of these output compounds and subsequent docking are hoped to avail drug candidates for synthesis and further studies, our goal being to avail compounds that would be effective in treating Chagas disease, and yet remain safe to the host in their mode of action.Not Submitted
Funder Acknowledgement(s): Grant #8G12MD007597 from NIMHD, NIH to RCMI program at Howard University, HU Advance-It grant from NSF, and Howard University College of Medicine Bridge Funds and Pilot Study Awards Program.
Faculty Advisor: Oladap Bakare and Yayin Fang, firstname.lastname@example.org