Bioisosteric transformation maps

Published by wallacei on 14 April 2012 - 3:27pm

Subject 

Request for Help

It is common in drug discovery to have a highly potent hit that has to be optimised to remove undesirable characteristics such as poor oral bioavailablity, metabolic stability or toxicity. In our case, we have a number of highly potent compounds that have quite a high LogP, which is considered a warning sign for both a promiscousity (i.e. binding to many compound targets in vitro) as well as poor oral bioavailabilty (as it breaks the Lipinski Rule of 5).
 
One approach to solving this issue is the concept of bioisosterism. From Wikipedia, http://en.wikipedia.org/wiki/Bioisostere "bioisosteres are substituents or groups with similar physical or chemical properties which produce broadly similar biological properties to a chemical compound. In drug design, the purpose of exchanging one bioisostere for another is to enhance the desired biological or physical properties of a compound without making significant changes in chemical structure."
One such example would be replacing a hydrogen with a flourine at a site of metabolic oxidation. "Because the fluorine atom is similar in size to the hydrogen atom the overall topology of the molecule is not significantly affected, leaving the desired biological activity unaffected. However, with a blocked pathway for metabolism, the drug candidate may have a longer half-life."
 
To that end I have created biosteric transformations using the Pipeline Pilot software programme for the compounds synthesized as part of this project. Two different approaches are implemented to generate the transformations:
1) Classic Biosteres involve transforming the original molecule based on a set of ~200 commonly used transfomrations, such as replacing a hydroxyl with a sufonamide. 
2) Database Biosteres involve transformations based on an algorithm described in this paper http://www.ncbi.nlm.nih.gov/pubmed/16562998
"M. Wagener, J.P.M. Lommerse, “The Quest for Bioisomeric Replacements”, J. Chem. Info. Modeling, 2006, 46(2), 677- 685"  
 
Focusing on just ZYH-3-1, I generated two reports (one for both methods) showing about 20 compounds resulting from such transformations that would all have ALogP < 5. It would be intereting to know how easy they would be to synthesize, as well as what would make sense to make based on what we know about the SAR of these compounds.
All the reports and data are available 
http://malaria.ourexperiment.org/in_silico_prediction/2954