Lipophilicity and biomimetic properties to support drug discovery

ABSTRACT

Introduction: Lipophilicity, expressed as the octanol-water partition coefficient, constitutes the most important property in drug action, influencing both pharmacokinetic and pharmacodynamics processes as well as drug toxicity. On the other hand, biomimetic properties defined as the retention outcome on HPLC columns containing a biological relevant agent, provide a considerable advance for rapid experimental – based estimation of ADME properties in early drug discovery stages.

Areas covered: This review highlights the paramount importance of lipophilicity in almost all aspects of drug action and safety. It outlines problems brought about by high lipophilicity and provides an overview of the drug-like metrics which incorporate lower limits or ranges of logP. The fundamental factors governing lipophilicity are compared to those involved in phospholipophilicity, assessed by Immobilized Artificial Membrane Chromatography (IAM). Finally, the contribution of biomimetic properties to assess plasma protein binding is evaluated.

Expert opinion: Lipophilicity and biomimetic properties have important distinct and overlapping roles in supporting the drug discovery process. Lipophilicity is unique in early drug design for library screening and for the identification of the most promising compounds to start with, while biomimetic properties are useful for the experimentally-based evaluation of ADME properties for the synthesized novel compounds, supporting the prioritization of drug candidates and guiding further synthesis.

KEYWORDS:

• ADME properties
• AGP chromatography
• biomimetic properties
• drug discovery
• druglikeness
• IAM chromatography
• HSA chromatography
• lipophilicity
• membrane permeability
• phospholipophilicity

Article highlights

• Lipophilicity is a key property in drug action and drug safety, included in most QSAR models for biological activity predictions.

• The minimum hydrophobicity concept implies cut off values and optimum lipophilicity ranges, incorporated in druglike metrics.

• Biomimetic properties as the retention outcome on IAM and protein –based HPLC stationary phases are useful for early ADME properties estimation.

• IAM retention is governed by both hydrophobic and electrostatic interactions and constitutes a border case between passive diffusion and binding.

• IAM chromatography can estimate intestinal permeability and blood brain barrier penetration in combination with additional physicochemical or molecular descriptors.

• HSA -HPLC provides estimates on binding to Human Serum Albumin and enables the construction and continuous update of databases to be used for the establishment of global HSA binding prediction models.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties

Additional information

Funding

This manuscript is not funded.