Drug-Like Property Concepts in Pharmaceutical Design

Abstract

The pharmaceutical industry is facing an ever increasing challenge to deliver safer and more effective medicines. Traditionally, drug discovery programs were driven solely by potency, regardless of the properties. As a result, the development of non-drug-like molecules was costly, had high risk and low success rate. To meet the challenges, the bar has been rising higher for drug candidates. They not only need to be active, but also drug-like to be advanced to clinical development. Drug-like properties, such as solubility, permeability, metabolic stability and transporter effects are of critical importance for the success of drug candidates. They affect oral bioavailability, metabolism, clearance, toxicity, as well as in vitro pharmacology. Insoluble and impermeable compounds can result in erroneous biological data and unreliable SAR in enzyme and cell-based assays. Rapid metabolism by enzymes and high efflux by transporters can lead to high clearance, short half-life, low systemic exposure and inadequate efficacy. Early property information helps teams make informed decisions and avoids wasting precious resources. Structure-property relationships are essential to guide structural modification to improve properties. High throughput ADME/TOX assays have been implemented and are being widely used to drive drug discovery projects in parallel with activity screening. Property design has become an integrated and inseparable part of the modern drug discovery paradigm. The approach has been proven to be a winning strategy.

Are the Sublimation Thermodynamics of Organic Molecules Predictable?

“…In recent years, it has been suggested that up to 40% of new drug molecules are effectively insoluble 15 and up to 75% are classified as having low solubility by the Biopharmaceutics Classification System (BCS). 16,9 At the lead optimization stage, it is not practical to carry out experimental determinations of thermodynamic solubility on large libraries of compounds. As a result, computational methods are employed to make predictions of numerous properties including solubility.…”

Driving efficiency in a high-throughput metabolic stability assay through a generic high-resolution accurate mass method and automated data mining

“…DMPK study for early drug discovery involves various automated in vitro assays such as metabolic stability, cytochrome P450 (CYP) inhibition and induction, and cell permeability study (Di et al, 2009). Metabolic stability is regarded as the most important frontline screen as it plays an important role in determining the overall pharmacokinetic properties of a new drug substance (Tolonen et al, 2009).…”

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“…If an orally administered drug is not sufficiently soluble, then it could not be fully absorbed into the blood circulation and will be expelled from the gastrointestinal tract before reaching its' site of action. Nevertheless, hydrophobicity and innate low-water solubility are gradually becoming rather unsurprising characteristics of early hits, lead compounds and even in some market-approved drugs.3 Nearly 60%-90% of the compounds that are currently being developed exhibit poor water-soluble features 3,4 and categorized under the Biopharmaceutical Classification System (BCS) classes II (low solubility and high permeability) and IV (low solubility and low permeability). [4][5][6] This is mainly because, most of the ligand-binding sites in the target proteins are secluded from the aqueous environment and hence hydrophobic compounds are generally preferred (or developed) in order to gain high binding affinity and activity against the target(s).…”

“…3 Nearly 60%-90% of the compounds that are currently being developed exhibit poor water-soluble features 3,4 and categorized under the Biopharmaceutical Classification System (BCS) classes II (low solubility and high permeability) and IV (low solubility and low permeability). [4][5][6] This is mainly because, most of the ligand-binding sites in the target proteins are secluded from the aqueous environment and hence hydrophobic compounds are generally preferred (or developed) in order to gain high binding affinity and activity against the target(s).…”

“…[4][5][6] This is mainly because, most of the ligand-binding sites in the target proteins are secluded from the aqueous environment and hence hydrophobic compounds are generally preferred (or developed) in order to gain high binding affinity and activity against the target(s). 3,7 In addition, recently, the drug discovery research is also seeing a paradigm shift from enzymes to more complicated therapeutic targets, such as ion channels, protein-protein interfaces, kinases and nuclear receptors.…”