Physical Properties in Drug Design

  • Robert J. YoungEmail author
Part of the Topics in Medicinal Chemistry book series (TMC, volume 9)


The physical properties of investigational molecules in drug discovery programmes have been the subjects of intense scrutiny, largely due to a propensity for the pursuit of examples where they are sub-optimal. This chapter introduces the noteworthy contributions that identified the shortcomings and then defines and discusses the key physical parameters (lipophilicity, pK a and solubility) and contemporary developments in their measurement and use. These physical characteristics impact the passage of a drug molecule from the administered dose to the site of action, profoundly influencing its pharmacokinetics and pharmacology. In particular, lipophilicity has a major influence on various parameters used to assess the developability of experimental molecules; the additional impact of aromaticity or flatness in structures and differentiation between the roles intrinsic (log P) and effective (log D) are also illustrated. In conclusion, the combined influences of good properties in efficient molecules are presented as powerful indicators of quality.


Physical properties Lipophilicity Hydrophobicity pKa Solubility log P log D Chromatographic hydrophocbity measurements Aromaticity Property forecast index Drug efficiency Ligand efficiency Ligand lipophilicity Efficiency Developability classification system Thermodynamics Structure property relationships Developability Attrition Permeation Cytochrome P450 hERG Promiscuity Plasma protein binding 



Absorption, distribution, metabolism and elimination


Blood–brain barrier


Binding efficiency index


Chromatographic hydrophobicity index


Chemiluminescent nitrogen detection


Calculated molar refraction


Developability classification system


Drug metabolism and pharmacokinetics


Fasted state simulated intestinal fluids


Fed state simulated intestinal fluids


General solubility equation




Human ether-a-go-go-related gene


Human serum albumin


Immobilised artificial membrane


Isothermal titration calorimetry


Ligand efficiency


Ligand lipophilicity efficiency


Melting point based absorption potential




Parallel artificial membrane permeation assays


Property forecast index


Quantitative estimate of drug-likeness


Quantitative structure activity relationships


Quantitative structure property relationships


Simulated gastric fluid


Size-independent ligand efficiency



The educational help of the many who have turned a maths-averse organic chemist into a medicinal chemist conversant in physical properties is gratefully acknowledged. In particular long-time friend and mentor Alan Hill has been the source of much knowledge and inspiration. The expertise of, and stimulating conversations with, Paul Leeson, Chris Luscombe, Darren Green, Mike Hann, Klára Valkó, Andrew Leach and Tim Ritchie have also contributed much to the growing debate and wider acceptance of the impact of physical properties.


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© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  1. 1.MDR Medicinal Chemistry, GlaxoSmithKline R&DStevenageUK

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