Basic Principles of Drug Discovery
Introduction and Necessary of Preclinical Studies & Clinical Trails
Drug discovery from original idea to final listing is an extremely complex process that always takes more than 12 years and cost over $1 billion. The initial research that occurs in academia provides the hypothesis that inhibition or activation of a protein or pathway presents a therapeutic effect against diseases. The drug-like small molecules or biotherapeutics are called candidate drugs. The candidate drug will then enter the pre-clinical stage for a series of tests. If successful, it will enter clinical development and eventually become a marketed drug.
Fig 1. Drug discovery process from target ID and validation through to filing of a compound and the approximate timescale for these processes. (Hughes, 2011)
Target identification and validation are one of the most important steps in new drug development. Drug target is defined as the biological entity that interacts with and is regulated by a specific compound. Early in-depth target selection and validation enables better understanding between target manipulation and disease efficacy so that increases the likelihood of clinical success. Bioinformatics-based data mining and phenotypic screening help to obtain potential disease-related targets. In general, target identification can be divided into target deconvolution and target discovery. Target-based screening strategy, phenotypic screening strategy, and fast-follower strategy are three classical drug discovery strategies for small molecules. Based on fast-developing technologies, a series of methods for target selection and validation have been developed.
Fig 2. Overview of drug discovery screening assays. (Hughes, 2011)
Once numbers of hits are obtained from high throughput screening (HTS) and virtual screening, this stage aims to refine these hits for more potent and selective compounds with improved drug efficacy, reduced off-target activity, and optimized physical and chemical/metabolic properties. The structure-activity relationship (SAR) research for each core compound structure allows the establishment of activity and selectivity of each compound. As a sensitive biophysical technique, NMR methodology has been widely applied in a hit and lead validation especially for the identification of weakly binding inhibitors and agonists that cannot be detected by plate-based spectrophotometric assays.
To better mimic the complex mechanisms of human diseases, there are standard preclinical and clinical approaches. Preclinical research aims to provide information about the safety and effectiveness of drug candidates before they are tested in humans. The basic research contains pharmacodynamics, pharmacokinetics, and toxicology. The ideal preclinical models include in vitro models, in vivo models, and in silico models. With further clinical trials, only 10% of all drugs become approved drugs.
Creative Biolabs has been a long-term expert in the field of drug discovery. As a pioneer and the undisrupted global leader, we offer a variety of products and services. Please do not hesitate to contact us for more detailed information.
Hughes, J.; et al. Principles of early drug discovery. British journal of pharmacology. 2011, 162(6): 1239-1249.