Computer Aided Drug Discovery offers effective inhibitors for specific cancer targets

The steps involved in Structure Based Drug Discovery

Indoleamine 2,3-dioxygenase is the rate limiting enzyme in tryptophan (Trp) catabolism. It catalyzes the oxidative degradation of L-tryptophan to Nformylkynurenine.  Because of this catabolic activity it has been postulated that one possible role of IDO is to inhibit the proliferation of intracellular pathogens  or tumor cells by depriving them of tryptophan.  Several human tumors express IDO, an enzyme which mediates immune escape in many cancer types.  The immunoregulatory potency of IDO became clear in 1998 when D. H. Munn, et al. demonstrated that IDO is a crucial component of the mechanism by which the allogeneic fetus protects itself from rejection by the maternal immune system. IDO contributes to the protection against autoimmunity, allergy, and the control of inflammatory pathology. Inhibition of the immune response is thought to be caused by the effect of IDO on T cells.  T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell mediated immunity.  They can be distinguished from other cell types by the presence of a special receptor on their cell surface called T cell receptors. T cells undergoing antigen-dependent activation  are exquisitely sensitive to local tryptophan catabolism, which causes them to arrest in  G1, become anergic, or die. Dendritic cells (DC) are suspected to be a crucial source of IDO. The protein is detectable and active in murine as well as human DCs.

Using Computer Assisted Structure Based Drug Discovery, molecular modeling researchers at the Swiss Insititute of Bioinformatics and researchers from Dr. Benoît J. Van den Eynde’ group  at the Ludwig Institute for Cancer Research Ltd (LICR) Brussels Branch have developed an approach exactly for generating the IDO inhibitors.  For the study, the researchers employed EADock algorithm. EADock uses a hybrid evolutionary algorithm with two fitness functions, in combination with a sophisticated management of the diversity.  EADock is interfaced with the CHARMM package for energy calculations and coordinate handling. The EADock was developed by the molecular modeling researchers at Swiss Institute of Bioinformatics over the last eight years.  The principle of dockcing  mainly deals with “lock and key” design, in which the active site regarded as a lock which can be fitted with a key, usually a small organic molecule which is able to regulate its activity. Once  interesting inhibitor molecules  has been obtained with docking, synthesis and laboratory experiments are necessary to confirm or reject the prediction.

In the current study of IDO, the scientists obtained  high success rates. Interesting fact  with this study is that fifty percent of the molecules designed in silico were active IDO inhibitors in vitro. Compounds that displayed activities in the low micromolar to nanomolar range, made them suitable for further testing in tumor cell experiments and for in vivo evaluation in mice. Success of the study may certainly help the scientists to begin evaluating the new compounds in patients undergoing cancer immunotherapy. According to Olivier Michielin, Assistant Member at the Lausanne Branch of LICR and leader of the SIB Swiss Institute of Bioinformatics Molecular Modeling group, “This is a satisfactory proof of principle showing that computational techniques can produce very effective inhibitors for specific cancer targets with high yield. This is very encouraging for future drug developments in the academic environment.”