A More Detailed Look at the Discovery and Pre-Clinical Phases of Drug R&D
Article by Derek DiRocco, PhD.
Pre-discovery research is concerned with identifying cellular signaling pathways and/or genomic or transcriptomic alterations that contribute to the development or progression of a disease ("target discovery"). This research includes mining of the knowledge base provided by published material that originated from government and academic labs, as well as any previous research by the company. Unfortunately, a lot of published data suggesting potential drug targets turn out to be dead ends. Years of work go into simply gaining a grasp on what particular cell process can be faithfully targeted, with scientific reproducibility, to effect disease initiation or progression. Once a fairly complete picture of the cellular and genetic processes underlying a disease is made, researchers will focus on individual targets in the process. Targets can be proteins, genes, or an intermediate form of RNA that can be altered by a therapeutic to modulate a disease.
Once a valid cellular process, protein, or gene has been determined as a valid target thousands of chemical compounds may be screened in order to find hits. A hit is likely a compound that can bind the target and act as an antagonist (inhibit) or agonist at the target (activate), depending on the goal of the research. Chemical compounds may be synthesized in a de novo process first using computational analysis to determine a chemical structure that will be predicted to bind to the biological target and then producing that compound through chemical synthesis. More commonly, available drug libraries are used in high throughput screening assays to obtain a few possible ‘lead’ molecules of interest to pursue out of thousands of tested chemicals.
Top lead molecules are then tested to determine the pharmacokinetic characteristics of the drug. These test cover how the lead molecules are Absorbed, Distributed, Metabolized, Excreted, and also how Toxic the drug is to the body (ADME/Tox). A compound passing these tests then moves on to be optimized further ("lead optimization"}. A lead compound can have parts of its chemical structure slightly tweaked leading to 100’s of analogues , or variations, of the original model molecule. These changes can alter binding of the drug to its target and other targets as well as how easily it can cross over a cell membrane or through the blood brain barrier. Toxicity in animal models is further evaluated at this stage. Each analogue is tested and retested and tweaked further in order to end up with what the scientists may consider an effective and safe lead candidate molecule.
With a few candidate molecules in mind testing moves into the preclinical testing phase. Experiments can be carried out in cellular models of the disease, in what are called treated in in vitro assays. Candidate molecules are also tested in laboratory animals for safety (Good Laboratory Practices [GLP] level toxicology, safety pharmacology, and genotoxicity studies) and also in animal models that attempt to replicate the human disease in order to determine potency and efficacy of the drug in order to treat the disease in a robust manner. Manufacturing and formulation efforts increase to be sure the drug compound can be delivered efficiently to its target and synthesized on a commercial scale according to Good Manufacturing Practices (GMP).
At this point in the drug discovery process, thousands of chemical molecules have been whittled down to only one or a few candidate chemical compounds, millions and millions of dollars have been invested and 3-6 years have gone by. Candidate therapeutics would now be ready to be tested in humans in the clinical phase of the drug development process.
Pre-discovery research is concerned with identifying cellular signaling pathways and/or genomic or transcriptomic alterations that contribute to the development or progression of a disease ("target discovery"). This research includes mining of the knowledge base provided by published material that originated from government and academic labs, as well as any previous research by the company. Unfortunately, a lot of published data suggesting potential drug targets turn out to be dead ends. Years of work go into simply gaining a grasp on what particular cell process can be faithfully targeted, with scientific reproducibility, to effect disease initiation or progression. Once a fairly complete picture of the cellular and genetic processes underlying a disease is made, researchers will focus on individual targets in the process. Targets can be proteins, genes, or an intermediate form of RNA that can be altered by a therapeutic to modulate a disease.
Once a valid cellular process, protein, or gene has been determined as a valid target thousands of chemical compounds may be screened in order to find hits. A hit is likely a compound that can bind the target and act as an antagonist (inhibit) or agonist at the target (activate), depending on the goal of the research. Chemical compounds may be synthesized in a de novo process first using computational analysis to determine a chemical structure that will be predicted to bind to the biological target and then producing that compound through chemical synthesis. More commonly, available drug libraries are used in high throughput screening assays to obtain a few possible ‘lead’ molecules of interest to pursue out of thousands of tested chemicals.
Top lead molecules are then tested to determine the pharmacokinetic characteristics of the drug. These test cover how the lead molecules are Absorbed, Distributed, Metabolized, Excreted, and also how Toxic the drug is to the body (ADME/Tox). A compound passing these tests then moves on to be optimized further ("lead optimization"}. A lead compound can have parts of its chemical structure slightly tweaked leading to 100’s of analogues , or variations, of the original model molecule. These changes can alter binding of the drug to its target and other targets as well as how easily it can cross over a cell membrane or through the blood brain barrier. Toxicity in animal models is further evaluated at this stage. Each analogue is tested and retested and tweaked further in order to end up with what the scientists may consider an effective and safe lead candidate molecule.
With a few candidate molecules in mind testing moves into the preclinical testing phase. Experiments can be carried out in cellular models of the disease, in what are called treated in in vitro assays. Candidate molecules are also tested in laboratory animals for safety (Good Laboratory Practices [GLP] level toxicology, safety pharmacology, and genotoxicity studies) and also in animal models that attempt to replicate the human disease in order to determine potency and efficacy of the drug in order to treat the disease in a robust manner. Manufacturing and formulation efforts increase to be sure the drug compound can be delivered efficiently to its target and synthesized on a commercial scale according to Good Manufacturing Practices (GMP).
At this point in the drug discovery process, thousands of chemical molecules have been whittled down to only one or a few candidate chemical compounds, millions and millions of dollars have been invested and 3-6 years have gone by. Candidate therapeutics would now be ready to be tested in humans in the clinical phase of the drug development process.