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The hidden art of drug development: How to create more potent drugs through synthetic analogs?
The process of drug development is like an adventure, with constant exploration and correction, and ultimately moving forward on the path to leading human health. Among these efforts, the H2L (Hit to Lead) stage plays an indispensable role. This is a process of using preliminary compound screening results through a limited optimization process to identify potential lead compounds.
The entire drug discovery process usually follows the following steps: target validation (TV) → assay development → high throughput screening (HTS) → H2L (Hit to Lead) → lead compound optimization (LO) → preclinical development → clinical Development. In the H2L stage, after the initial screening compounds are confirmed and evaluated, they are expanded to synthetic analogs to increase the number of effective candidate compounds.
Compounds identified in the primary screening generally have binding affinities in the micromolar (10-6 M) range for biological targets, and through limited H2L optimization, the affinities of these compounds are often It can be increased by several orders of magnitude, reaching the nanomolar (10-9 M) range.
In the H2L stage, the "hit" compounds from the initial screening need to be confirmed first. This process includes several important methods, such as confirmation testing, dose-response curves, orthogonal testing, secondary screening, etc. These tests help researchers determine the efficacy of a compound and its selectivity for a biological target.
One study shows that for every 5,000 potential compounds, only one successfully enters clinical development and eventually becomes an approved drug.
Confirmation and Extension
Once a “hit” is confirmed, the team will select several new compound clusters for further exploration based on the results of various tests. Ideal compound clusters typically have the following characteristics: high affinity for the target (less than 1 μM), selectivity for other targets, significant efficacy in cell-based assays, and good drug-likeness indicators. Next, the researchers will begin synthesizing different similar compounds to understand their structure-activity relationships (QSAR).
During drug synthesis, medicinal chemists use combinatorial chemistry, high-throughput chemistry or classical organic chemistry methods to synthesize related compounds.
Pilot Optimization Phase
Entering the stage of lead compound optimization, the goal is to synthesize compounds with higher potency, reduced off-target activity and reasonable in vivo pharmacokinetic predictions. This optimization process is achieved through chemical modification of the “hit” structures, based on structural information obtained from structure-activity relationships (SAR) and structure-based design.
The research team will conduct experimental tests in animal models and perform ADMET (in vitro and in vivo pharmacokinetic) analysis to confirm the efficacy and safety of the compounds.
Best Practices
For educational purposes, the European Federation of Medicinal Chemistry and Chemical Biology (EFMC) shares a series of webinars including Best Practices in Hit Finding and Case Studies in Hit Generation.
In this scientific adventure of pursuing innovation, the process of synthesizing analogs is not only a technical challenge, but also an important mission to improve human health. What hidden arts are waiting to be discovered in future drug design?
