From the computer to the clinic and back
The use of computational modeling in drug discovery and development in ubiquitous in academia and industry. A crucial element for the success of such efforts is the tight integration of all aspects of drug discovery element, ranging from biologists through chemists to clinicians. In this presentation, some case studies of such joint efforts are discussed.
The clinical observation of multiple artemisinin-resistant strains of P. faciliparum in several southeast asian countries raises the specter to reverse the significant gains that were made in the treatment of malaria in the last two decades. A significant hurdle in addressing this problem is that the mechanism of action of artemisinin is not well understood. A new hypotheses of the MOA of artemisinin is discussed with an emphasis on the development of a structural models to explain the experimental observations and the application towards the discovery and development towards a new class of malaria drugs.
In the second part of the talk, the computational design of chemical probes for epigenetic writers and erasers in the acetylome are discussed. Starting from our early work on structural models of histone deacetylases (HDACs), I will describe novel approaches to isoform selective HDAC and histone acetyl transferase (HAT) modulators. Finally, the application of HDAC inhibitors to treat Niemann-Pick Type C, a rare and fatal lysosomal storage disorder, that was tested in recently completed clinical trial will be discussed.