Hit to Lead and PCC

In innovative drug discovery based on targets, we have identified the targets, established a screening evaluation system, conducted high-throughput screening or other methods to obtain some active compounds, and these active compounds can be called: Hits. Usually In other words, the mainstream of high-throughput screening (HTS) is the use of economical and rapid chemical biology methods, such as ALPHA technology, TR-FRET technology, and FP technology. One problem is that these assays are susceptible to interference from PAINS compounds due to the limitation of their principle of action. For example, some compounds are “protein killers”, such as the quencher of singlet oxygen in ALPHA; the mimic of biotin in TR-FRET; in FP, the compound itself interferes with fluorescence absorption. Therefore, the Hits stage is still far from our goal. So after the next “cherry pick”, came the important part: Hit validation. Here, I must shout out a slogan: Primary screen is not a problem, the key point is the validation. In the development of innovative drugs, we should make bold assumptions and carefully verify. A large number of verification experiments, such as physical and biological methods SPR, ITC, NMR and other comprehensive verification methods must be vigorously developed and verified in multiple dimensions. When a sprout compound is verified and determined to be a real hit, it can proceed to the next stage-the lead compound stage.

Lead compounds, as the source of new drug discovery, need to consider a little more things at this stage: look at how the skeleton is, whether there is room for modification, and look at the medicinal properties of the structure. Therefore, in the early target-based innovative drug discovery process, based on the requirements of MOA and Validation, the early drug discovery must be led by biologists. After entering the lead compound stage, this time requires the strong intervention of medicinal chemists. Obtaining a good lead compound alone is only the first step in the long march. In addition to the most subjective activity issues, more matrix drug-forming properties, water solubility, fat solubility, metabolic stability, safety, etc., are all important. It is no exaggeration to say that in order to overcome and solve a certain problem, “fallin love” is not enough, and the input of “heart and soul” is needed. Every possibility and every detail needs to be optimized for delicate. Therefore, lead optimization is the core link of drug discovery. Of course, the biological team must be able to provide strong support. If the structure of the crystal complex can be obtained, coupled with the participation of the CADD team, and in-depth research on structure-effect SAR/QSAR, it will surely be able to quickly advance the project. It is worth pointing out that the research and development of new drugs may be led by medicinal chemists, but the development of innovative drugs must and must be the close collaboration and efficient cooperation of biologists and medicinal chemists.

When the lead compound is continuously optimized and the structure and effect are clear. At the molecular level, it can reach single-digit nM levels, and the cell level can reach more than ten or tens of nM levels. Animal toxicology and effectiveness experiments are also good. The protein, cell, and animal levels have certain relevance, and the most important medicine skeleton should be a good PCC. Of course, this is only a general case. Just like how to determine a target as a drug target, when a target becomes a drug, it should be a definite drug target. A PCC ultimately returns to safety and effectiveness. Most of the existing drugs do not know their targets and mechanisms of action, and can still cure diseases and save people and serve humanity.

Related Articles:

Discovery and Optimization of Lead Compounds

Hit Identification in Drug Discovery