Screening for Drug-like Properties
Your program will benefit tremendously from optimization of absorption, distribution, metabolism, excretion, and toxicity properties (ADME/Tox) of your compounds in addition to pharmacology (efficacy and selectivity).
Christopher Lipinski has commented: Drug-like is defined as those compounds that have sufficiently acceptable ADME properties and sufficiently acceptable toxicity properties to survive through the completion of human Phase I clinical trials (1).
While the primary goal of the your drug development program is to discover high-affinity ligands against the target protein you also need to monitor for drug-like properties. Major source of failure of drug candidates in development phase - as high as 4 drug candidates out of 10 - is due to poor biopharmaceutical properties (2).
High-activity leads are a precious commodity and elimination of high affinity ligand with unsuitable properties can be a startling challenge to the project as well as to your personal career and goals! The good news is that a number of new technologies was developed to address the problem of attrition of drug candidates during the development phase.
Probably the most important advance in recent years was an understanding that structural, physicochemical, and biochemical properties of the small molecule drug leads are excellent predictors of ADME/Tox properties. Moreover these drug-like properties are excellent predictors of the compounds becoming successful drug products.
Most important drug-like properties include:
- Lipophilicity
- pKa
- Solubility
- Permeability
- Chemical Stability
- Metabolic stability
- Protein and tissue binding
- Cell transport (uptake, efflux)
- Drug-drug interactions
- Genotoxicity
- Cardiotoxicity
- and other properties
The great news for your project is that the properties above can be measured in vitro at greatly reduced expense, time, and animal usage compared to the classic ADME/Tox methods. Combining structure-activity screening with drug-like profiling will allow you to develop holistic approach where you can balance activity and properties in order to produce the best drug product (2, 3).
With a robust system for drug-like property profiling you can achieve multiple goals:
- Rapidly evaluate of compounds as available from synthesis or HTS
- Rank order compounds for drug-like properties
- Guide synthetic optimization of properties in parallel with activity
- Allocate resources to the most promising leads
- Assess risk of problems with ADME, formulation, stability, or process
- Reduce costly delays on compounds with inadequate properties
- Select compounds for in vivo studies of bioactivity and pharmacokinetics
References:
- Lipinski C.A. (2000). Drug-like properties and the causes of poor solubility and poor permeability. Journal of Pharmacological and Toxicological Methods, 44, 235-249.
- Kerns E.H. (2001). High Throughput Physicochemical Profiling for Drug Discovery. Journal of Pharmaceutical Sciences, 90, 1838-1858.
- Kerns E.H. and Di L. (2008). Drug-like properties: Concepts, structure design and methods. Burlington, MA: Academic Press
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Recommended ADME/Tox assays for different phases of drug discovery project
Pre-Exploratory
Target Validation
In silico analysis
Early Exploratory - Confirmed Hits
Purity
Integrity
Late Exploratory - Advanced Hits
Stability
Permeability
Metabolism
CYP (P450) Inhibition
Discovery - Lead Series
Stability
PAMPA
Caco-2 Permeability
PAMPA-BBB
Metabolism
CYP IC50
Pharmacokinetics
Pre-Development - Candidate
In vivo toxicology
Development
Successful Drug=Potency+Properties
Reference: Kerns E.H. and Di L. (2008). Drug-like properties: Concepts, structure design and methods. Burlington, MA: Academic Press.