SEP 24, 2014 12:00 PM PDT

The Accurate Prediction of Ligand Binding Free Energies

  • Principal at Disruptive Biomedical, LLC, Professor of Practice at MIT & Northwestern
      Mark Murcko is Principal at Disruptive Biomedical, serving as an independent consultant as well as a Professor of Practice at MIT. Until 2011 Mark was CTO and Chair of the Scientific Advisory Board at Vertex Pharmaceuticals, and responsible for incorporation of disruptive technologies across global R&D.  He is co-inventor of Incivek (telaprevir) as well as Agenerase (amprenavir) and Lexiva (fosamprenavir) for HIV. In addition, he guided the early efforts of Vertex's cystic fibrosis program that produced Kalydeco (ivacaftor) and multiple other CF compounds currently in late-stage development.  Mark is also a co-inventor of 8 other clinical candidates for cancer, inflammation and infectious disease.  Prior to Vertex, Mark worked at Merck Sharpe & Dohme where he worked on the carbonic anhydrase program that produced the glaucoma drug Trusopt (dorzolamide). He was the co-organizer of the 2008 ACS National Medicinal Chemistry Symposium and served as Chair of the 2013 Gordon Research Conference in Medicinal Chemistry.

    In the past decade, we have witnessed an explosion in the availability of high-resolution structural information that sheds light on the binding of diverse classes of ligands to both soluble proteins and integral membrane receptors. From orthosterics to allosterics, from tiny fragments to enormous rule-breakers, we know more than ever about how ligands bind. However, the ability to accurately predict binding free energies has lagged behind, significantly limiting the utility of this structural information. The good news is that in the past few years there has been a breakthrough in ligand binding free energy prediction. I will summarize the evidence and suggest ways to effectively deploy this new capability

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