A Bioavailability Score

Abstract

Responding to a demonstrated need for scientists to forecast the permeability and bioavailability (F) properties of compounds before their purchase, synthesis, or advanced testing, we have developed a score that assigns the probability that a compound will have F > 10% in the rat. Neither the rule-of-five, log P, log D, nor the combination of the number of rotatable bonds and polar surface area successfully categorized compounds. Instead, different properties govern the bioavailability of compounds depending on their predominant charge at biological pH. The fraction of anions with >10% F falls from 85% if the polar surface area (PSA) is < or = 75 A(2), to 56% if 75 < PSA < 150 A(2), to 11% if PSA is > or = 150 A(2). On the other hand, whereas 55% of the neutral, zwitterionic, or cationic compounds that pass the rule-of-five have >10% F, only 17% of those that fail have > 10% F. This same categorization distinguishes compounds that are poorly permeable from those that are permeable in Caco-2 cells. Further validation is provided with human bioavailability values from the literature.

ADME Evaluation in Drug Discovery. 6. Can Oral Bioavailability in Humans Be Effectively Predicted by Simple Molecular Property-Based Rules?

“…Recently, Martin proposed a score to predict bioavailability based on several molecular properties, including polar surface area (PSA), Rule of Five, and molecular charged state. 4 The authors believed that the bioavailability score might be used in very early drug discovery for selecting compounds to purchase or synthesize. Generally, Veber's work as well as Lu's work and Martin's work supports the same conclusion: bioavailability may be well predicted by simple molecular properties.…”

Screening in a spirit haunted world

“…Lipinski's now famous rules [1] focused on the physical properties of drugs, reacting to an early tendency in HTS libraries toward large and hydrophobic molecules that were unlikely to be orally bioavailable. Subsequent studies, typically using retrospective analysis of hit lists, have focused on chemical reactivity [2], assay interference [3], high flexibility [4], oxidation potential [5], formal molecular charge [6], or liability to degradation and precipitation [7]. Indeed, these characteristics have been incorporated at most pharmaceutical companies using computational filters that flag likely nuisance compounds in screening collections, so that they can be scrutinized when reviewing screening hit lists.…”

Unexpected plant-systemic insecticidal properties of alkylene-tethered bis-imidacloprid derivatives

“…29) In addition, ionizable molecules such as glyphosate could not follow the rule as do neutral molecules, considering that the solubility and log P of ionic molecules are pH-dependent. 30) The divalent neonicotinoids elicit excitatory toxicity signs similar to monovalent compounds. 11,14,16) They are not ionic and bear the essential specific functional groups common to their monovalent counterparts.…”