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The secret dance of drug discovery: How to find tomorrow's star among many compounds?
In the new drug discovery process, "Hit to Lead" (H2L) is an important stage, which represents the beginning of the evaluation of small molecule compounds selected from high-throughput screening (HTS). Series of steps. At this stage, researchers will confirm the "hit" compounds initially screened and perform limited optimization to find possible lead compounds. These lead compounds will further enter the next step of drug discovery: Lead Optimization (LO) ). The entire drug discovery process generally follows the following path: target validation (TV) → assay development → high-throughput screening (HTS) → hit-to-lead (H2L) → lead compound optimization (LO) → preclinical development → clinical development.
In the Hit to Lead stage, researchers usually face a very challenging task. Only every 5,000 compounds that enter drug discovery and enter pre-clinical development may eventually become an approved drug.
At this stage, the first step is to confirm and evaluate the initial compounds screened by HTS. These validations typically include test-retest, dose-response curves, orthogonal testing, and functional cell testing. Through these methods, researchers can ensure the activity and reproducibility of screened compounds on specific biological targets.
Typically, compounds from these initial screens display binding affinities for their biological targets in the micromolar concentration range, and after limited H2L optimization, these affinities can often be improved to the nanomolar range.
With the "Strike Confirmation" process completed, the next step is "Strike Expansion". At this point, the research team will select several clusters of compounds that demonstrate high affinity, selectivity, and effectiveness based on confirmed compound characteristics. Ideal clusters of compounds typically also require drug similarity, low to moderate binding to human serum albumin, and low interference with P450 enzymes and P-glycoprotein.
Among the selected compounds, emphasis will be placed on the feasibility of synthesis, the stability of the compound and its performance in animal models, which are indispensable elements in the process of new drug discovery.
After the H2L phase, researchers will select three to six compound series for more in-depth exploration, including testing of quantitative structure-activity relationships (QSAR). Central to this phase is the development of lead compounds with improved activity, reduced side effects and suitable pharmacokinetics. This means that the structure of the compound will be adjusted at the molecular level based on existing knowledge of structure-activity relationships.
At this stage, researchers not only need to rely on chemical optimization strategies, but also conduct experimental tests on animal effectiveness models. Such measures can ensure the feasibility and effectiveness of the final drug in clinical applications.
In the drug discovery process, especially the H2L stage, good practices are indispensable. For educational purposes, the European Federation of Medicinal Chemistry and Chemical Biology (EFMC) has shared a series of webinars, including "Best Practices in Strike Discovery" and "Case Studies in Strike Generation."
With the advancement of science and technology, the means of compound screening and optimization will become more and more diverse, and we may witness revolutionary changes in drug discovery in the next few years. But in this seemingly certain process, how many hidden challenges are still waiting for us to overcome?
