In building this blog, I searched for my old medical science blog that I maintained in 2008, my last year or so of graduate school. Here is one of the articles I published back then that is still relevant…
Drug discovery is a very complex process which entails discovering new agents for the treatment or prevention of diseases and disorders. Despite the high level of advances in the understanding of the human body, from basic human physiology to the smallest level of the human genome, a potential agent still takes an upward of 15 years from pre-clinical study in the lab to the patient lying in a hospital. Only in understanding the various strategies that have been implemented for the development of clinically successful agents can one find the best approach for effective drug discovery. Recently, new terms have been coined to describe two approaches to the study of the interaction between organisms and chemical molecules used to alter the biochemical function of molecular targets: forward and reverse pharmacology.
Much of the drug discovery and development that is carried on today is based on forward pharmacology. In this approach, a molecular target instrumental in modulating an abnormal biological process is first identified. One then searches for a molecule that can either positively or negatively modulate this target, depending on the desired clinical outcome. Then is often through the use of high-throughput screening of compound libraries, using the molecular target as “bait” to “hook” the potential therapeutic agent. Forward pharmacology is thus simply a target-based strategy.
Conversely, in reverse pharmacology, agents that have a history of therapeutic activity are used as a starting point for drug discovery. Documented medicinal compounds, often from traditional natural sources, have their active ingredients isolated, and these molecules are the basis for drug discovery. Reverse pharmacology often operates on three consecutive levels: experiential, exploratory, and experimental. Pharmacoepidemiology, or the study of the effects of drugs in a large human population, constitutes experiential reverse pharmacology. Information on traditional medicine including the illness or disease it is used to treat and any potential side effects are gathered. In exploratory reverse pharmacology, extensive scientific study is conducted on these compounds to learn the mechanism of action and the targets of these agents. Human dose determination studies are also sometimes conducted. Experimental reverse pharmacology involves the opitmization of these chemical entities using computational chemistry to maximize activity, potency, or water solubility.
There are many advantage and disadvantage to forward and reverse pharmacology approaches. Forward pharmacology is often attractive due to the advances in the technology associated with high-throughput screening and the large compound libraries that have been constructed. However, an inherent disadvantage of forward pharmacology is that drugs are discovered exclusively on their ability to target specific cellular molecules. Billions of dollars are spent within the pharmaceutical industry developing potential drugs which be successful in pre-clinical models but fail in clinical studies due to toxicity, unfavorable pharmacokinetics, or lack of target validation. Because of this, a large number of drug candidates may be identified in the pre-clinical discovery period but only 1-5% reaching the end phases of clnical trials due to numerous bottlenecks. Additionally, the big pharmaceutical industry sometimes only focus on discovery agents that modulate long established targets instead of new targets because of the risk of failure. These are some areas where reverse pharmacology is favorable. Since agents with therapeutic success is studied in the reverse approach, a sense of the pharmaceodynamic and pharmacokinetic properties are known and new targets have the potential to be validated. This can also lead to a shorter duration between drug discovery and drug marketing. Also, due to these factors and the use of computational chemistry, there is a great chance for there to be a greater number of compounds entering clinical trials compared to those in pre-clinical study. There are some drawbacks to reverse pharmacology, however. Often times, these agents may have multiple targets that are never identified and assays to validate these compounds are often phenotypic (i.e. pain reduction, decrease in blood pressure, reduction of tumor size).
All in all, both forward and reverse pharmacology approaches have a place in drug discovery. However, all factors must be taken into consideration to determine which approach is best.
Pharmacology at a reverse
Chemical complemenation: A definitive phenotypic strategy