title: Thermodynamic Proxies to Compensate for Biases in Drug Discovery Methods.
abstract: OBJECTIVE
  We propose a framework with simple proxies to dissect the relative energy contributions responsible for standard drug discovery binding activity.
  
  
  METHODS
  We explore a rule of thumb using hydrogen-bond donors, hydrogen-bond acceptors and rotatable bonds as relative proxies for the thermodynamic terms. We apply this methodology to several datasets (e.g., multiple small molecules profiled against kinases, Mycobacterium tuberculosis (Mtb) high throughput screening (HTS) and structure based drug design (SBDD) derived compounds, and FDA approved drugs).
  
  
  RESULTS
  We found that Mtb active compounds developed through SBDD methods had statistically significantly larger PEnthalpy values than HTS derived compounds, suggesting these compounds had relatively more hydrogen bond donor and hydrogen bond acceptors compared to rotatable bonds. In recent FDA approved medicines we found that compounds identified via target-based approaches had a more balanced enthalpic relationship between these descriptors compared to compounds identified via phenotypic screens
  
  
  CONCLUSIONS
  As it is common to experimentally optimize directly for total binding energy, these computational methods provide alternative calculations and approaches useful for compound optimization alongside other common metrics in available software and databases.
authors: Collaborative Drug Discovery, Inc., 1633 Bayshore Highway Suite 342, Burlingame, California, 94010, USA. ekinssean@yahoo.com.|Collaborations in Chemistry, 5616 Hilltop Needmore Road, Fuquay Varina, North Carolina, 27526, USA. ekinssean@yahoo.com.
authors: Sean
authors: S
authors: Ekins
authors: Collaborative Drug Discovery, Inc., 1633 Bayshore Highway Suite 342, Burlingame, California, 94010, USA.
authors: Nadia K
authors: NK
authors: Litterman
authors: , 10 Connshire Drive, Waterford, Connecticut, 06385-4122, USA.
authors: Christopher A
authors: CA
authors: Lipinski
authors: Collaborative Drug Discovery, Inc., 1633 Bayshore Highway Suite 342, Burlingame, California, 94010, USA.
authors: Barry A
authors: BA
authors: Bunin
mesh_terms: D019295:Computational Biology; D016208:Databases, Factual; D055808:Drug Discovery / Q000379:methods*; D019277:Entropy; D057166:High-Throughput Screening Assays; D006860:Hydrogen Bonding; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D010770:Phosphotransferases / Q000737:chemistry; D011955:Receptors, Drug / Q000737:chemistry; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: D011955:Receptors, Drug; D054852:Small Molecule Libraries; D010770:Phosphotransferases
keywords: enthalpy; entropy; high-throughput screening; structure based drug design; tuberculosis