NSC3332452 compound docked to 1MS8 (TcTS).


Jenny Liang, PRIME 2012 (Malaysia)

Chagas disease is a tropical malady characterized by cardiovascular and gastrointestinal complications in the chronic stages. Prevalent in regions of Mexico, Central and South Americas, Chagas originates from infection by Trypanosoma Cruzi, a protozoan parasite transmitted via contact with triatomine insect feces and contaminated bodily fluids. While the acute phase is largely asymptomatic, chronic Chagas disease includes heart and digestive abnormalities followed by death. Existing treatments with Nifurtimox and Benznidazole are effective in acute phases, but are limited in the chronic stages and often have detrimental side effects.

The purpose of the project is to apply an in-silico approach to identify natural and synthetic compounds that may act as inhibitors of essential proteins in the Trypanosoma Cruzi proteome. Our focus is mainly on molecules derived from natural products which often display specific biological activity and have highly diverse stereochemistry. We docked these compounds to proteins and evaluated the possible interactions between individual amino acids comprising the protein active site and natural product derivative in hopes of contributing to the development of a more effective, efficient and safe treatment for Trypanosoma Cruzi infection, while halting disease progression (see Figure).

In this computational approach, glycosylphosphatidylinositol (GPI)-anchored surface enzymes, Trans-sialidase (TcTS) and gp63 are of interest. The literature indicates these proteins play vital roles in cell infection, including evasion from the host immune system, cell-to-cell communication, cell penetration, and the attachment of parasites to host receptors. Protein crystal structures 1MS8 (TcTS) and 1LML (gp63) were selected for analysis from the RCSB Protein Data Bank (PDB) based on molecule type, resolution, location of missing residues and complexed ligands. Using Autodock 3.0, a program used to predict the binding of flexible ligands (small molecules) to designated 3-D receptors, natural compounds from the Universiti Sains Malaysia’s Nature-Based Drug Discovery System (NADI) and synthetic compounds from the National Cancer Institute (NCI) databases were docked between 100 to 1,000 times to these crystal structures using a computational virtual screening approach (see Figure). SMAP, a software tool designed for binding pocket similarity search, determined the specificity of these compounds to TcTS and gp63 by screening the Trypanosoma Cruzi proteome for structurally similar proteins. However, available PDB crystal structures only represented a small portion of the entire set of proteins comprising the Trypanosoma Cruzi proteome. The addition of homology structures to the screened library would provide a more accurate prediction of proteome targets.

With the results of the virtual screening, in-vitro assays can test the efficacy of our predicted top NADI and NCI compounds in inhibiting Trypanosoma Cruzi development. The use of NADI serves as a step towards in-silico drug discovery with natural resources. Results would greatly contribute to further drug development for the treatment of Chagas disease and Trypanosoma Cruzi research.

PARTICIPATING RESEARCHERS: USM: Sy Bing Choi, Habibah Wahab; UCSD: Philip Bourne, Li Xie, Chirag Krishna