Lipophilicity and biomimetic properties to support drug discovery

Abstract

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.

Gold(I) bis(N‐heterocyclic carbene) complexes: Metabolic stability, in vitro inhibition, and genotoxicity

“…We also investigated a possible explanation for the difference in metabolism by estimating and comparing the lipophilicity of the two compounds. This parameter is important, because it is not only used to estimate drug permeation, but it can also be used to assess the clearance of a compound, since more lipophilic compounds have a greater affinity for metabolic enzymes . The calculation is consistent with our observation that the homo‐bis(NHC) complex 1 has a lower half‐life compared to hetero‐bis(NHC) complex 2 , which implies higher affinity for the metabolic enzymes in the liver microsomes due to higher estimated lipophilicity (4.80 vs 4.25 respectively).…”

Is there enough focus on lipophilicity in drug discovery?

“…In practice, the calculated log P (clog P) is often used instead of the measured log P as an assessment of lipophilicity, with measured partition coefficients obtained on key compounds through a project's progression. Since clog P values used for screening virtual libraries are often inaccurate, this can lead to imprecise results that cause promising compounds to be abandoned and/or flawed compounds to move forward [3,4]. Comparisons made between marketed oral drugs and compounds in earlier stages of development indicate that log P values beyond Lipinksi's rule-of-five criteria (>5) are associated with undesired drug features, such as rapid metabolic turnover, poor aqueous solubility, high plasma protein binding, and tissue accumulation.…”

“…Additionally, log P should be experimentally evaluated for a representative set of compounds in order to predict log P for a given chemical series. This can be accomplished using chromatographic techniques such as reversed-phase high performance liquid chromatography [3,4]. The use of confidence in log P prediction would allow higher resolution and discrimination with regard to selection of reliable and non-reliable predictions, thus increasing design efficiency.…”

Revisiting the application of Immobilized Artificial Membrane (IAM) chromatography to estimate in vivo distribution properties of drug discovery compounds based on the model of marketed drugs

“…The application of IAM chromatography as an aid in drug discovery has been reviewed extensively in recent years [4][5][6][7][8]. The molecular factors that influence IAM retention have also been discussed [9,10].…”

“…Drug efficiency and potency enables early dose estimation as drug efficiency approximates to the proportion of free drug concentration and dose [19]. log DRUG eff = 2 -(0.23 log K (HSA) + 0.43 log K (IAM) -0.72) (6) It has been found that basic compounds that have CHI (IAM) value greater than 50 have phospholipidosis potential [20] and also show promiscuous binding, interacting with several targets, causing potential toxicity and side effects [21].…”