Hydration Free Energy as a Molecular Descriptor in Drug Design: A Feasibility Study

Zafar, Ayesha; Reynisson, Jóhannes

Abstract

In this work the idea was investigated whether calculated hydration energy (ΔGhyd) can be used as a molecular descriptor in defining promising regions of chemical space for drug design. Calculating ΔGhyd using the Density Solvation Model (SMD) in conjunction with the density functional theory (DFT) gave an excellent correlation with experimental values. Furthermore, calculated ΔGhyd correlates reasonably well with experimental water solubility (r2=0.545) and also log P (r2=0.530). Three compound collections were used: Known drugs (n=150), drug-like compounds (n=100) and simple organic compounds (n=140). As an approximation only molecules, which do not de/protonate at physiological pH were considered. A relatively broad distribution was seen for the known drugs with an average at −15.3 kcal/mol and a standard deviation of 7.5 kcal/mol. Interestingly, much lower averages were found for the drug-like compounds (−7.5 kcal/mol) and the simple organic compounds (−3.1 kcal/mol) with tighter distributions; 4.3 and 3.2 kcal/mol, respectively. This trend was not observed for these collections when calculated log P and log S values were used. The considerable greater exothermic ΔGhyd average for the known drugs clearly indicates in order to develop a successful drug candidate value of ΔGhyd<−5 kcal/mol or less is preferable.

Citation

Zafar, A., & Reynisson, J. (2016). Hydration Free Energy as a Molecular Descriptor in Drug Design: A Feasibility Study. Molecular Informatics, 35(5), 207-214. https://doi.org/10.1002/minf.201501035

• Journal Article Type: Article
• Online Publication Date: Apr 13, 2016
• Publication Date: 2016-05
• Deposit Date: Jun 12, 2023
• Journal: Molecular Informatics
• Print ISSN: 1868-1743
• Publisher: Wiley-VCH Verlag
• Peer Reviewed: Peer Reviewed
• Volume: 35
• Issue: 5
• Pages: 207-214
• DOI: https://doi.org/10.1002/minf.201501035
• Keywords: Organic Chemistry; Computer Science Applications; Drug Discovery; Molecular Medicine; Structural Biology