Thermodynamic Proxies to Compensate for Biases in Drug Discovery Methods

Pharm Res. 2016 Jan;33(1):194-205. doi: 10.1007/s11095-015-1779-y. Epub 2015 Aug 27.


Purpose: 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.

Keywords: enthalpy; entropy; high-throughput screening; structure based drug design; tuberculosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Computational Biology
  • Databases, Factual
  • Drug Discovery / methods*
  • Entropy
  • High-Throughput Screening Assays
  • Hydrogen Bonding
  • Mycobacterium tuberculosis / drug effects
  • Phosphotransferases / chemistry
  • Receptors, Drug / chemistry
  • Small Molecule Libraries
  • Structure-Activity Relationship
  • Thermodynamics*


  • Receptors, Drug
  • Small Molecule Libraries
  • Phosphotransferases