Date: April 20, 2015
Source: Stony Brook University
A new mathematical model that uses drug-target kinetics to predict how drugs work in vivo may provide a foundation to improve drug discovery, which is frequently hampered by the inability to predict effective doses of drugs, researchers report..
Drugs normally work by binding to proteins in the human body. In the process of discovering new drugs, investigators try to ensure that a drug binds much more tightly to the desired protein target, rather than binding to other off-target proteins, which cause drug toxicity and/or side effects in patient. This difference in binding is thought to control the therapeutic index or window of a drug. The "window" is the difference in concentration of a drug that causes the desired therapeutic effect, compared to the concentration that causes toxicity. An insufficient therapeutic window is often the principal reason for drug failure in clinical trials.
"Current methods utilized in drug discovery are unable to account for the fact that in vivo drug levels fluctuate, which is a major factor in the failure to accurately predict drug action in vivo," explained Dr. Tonge. "We have created a mathematical model that accurately predicts drug activity based not only on how strongly the drug binds to the protein target, but also on how long the drug remains bound to the target."
The researchers validated their approach by successfully predicting the in vivo activity of an antibacterial agent that targets the human pathogen Pseudomonas aeruginosa.
Dr. Tonge says the approach, which is the first mechanistic pharmacokinetic-pharmacodynamic model that integrates precise measurements of enzyme inhibition (or drug-target kinetics), is applicable not only to other drug targets in the area of infectious diseases but also to targets in all other disease areas.
"We believe the model and entire approach will significantly improve the selection and development of drug candidates," he added, "and also improve our ability to develop chemical tools for dissecting and understanding cellular biology." As a next step to realizing this vision, Professor Tonge has recently founded a company on this concept, Chronus Pharmaceuticals, Inc., with his colleague and co-lead author Dr. Stewart Fisher.
