The determination of the lead compound is by no means a simple "sieve activity"

Among them, the pharmacophore model method in computer-aided drug design is an important indirect drug design method that can be used for the discovery of lead compounds
.
The rapid development of computer and information technology, and the application of computer graphics technology in the field of drug research have led to the development of the concept of pharmacophore models
.
Medicinal chemists not only pay attention to the properties of the pharmacophore itself, but also attach great importance to the spatial relationship between the pharmacophores
.
Another kind of molecular docking technology refers to the technology in which two or more molecular models form the best combination through the matching of geometric shapes, chemical environment and energy in a molecular simulation environment
.
Virtual screening of molecular docking requires three-dimensional structure information of target biological macromolecules and small molecular compounds
.
First, establish a database of a large number of three-dimensional structures of compounds, and then "docking" the molecules in the library one by one with the target molecules.
By continuously optimizing the position (orientation) of the small molecule compound and the dihedral angle (conformation) of the flexible bond inside the molecule, search The optimal conformation of the interaction between the small molecule compound and the target macromolecule is calculated, and the interaction and binding energy are calculated.
As long as the compound in the database has sufficient molecular diversity, it is possible to search for the ideal molecular structure from the library
.

Synthesis and Screening Technology of DNA Encoding Small Molecule Compound Library

This technology uses combinatorial chemistry methods and the diversity and scalability characteristics of DNA coding to quickly provide lead compounds for the decisive early stage of drug development, thereby accelerating the development of new drugs
.
Compared with traditional high-throughput screening of million-level compound libraries, DNA-encoded compound libraries have greatly increased the number of compounds and the coverage of diversity
.
At the same time, because each compound has a DNA code to facilitate identification and screening results, the entire compound library (not just a single compound) can be used for incubation and affinity screening with biological targets
.
Since the compounds screened by this technology are the result of most compounds competing with screening targets, their activity is relatively high.
At the same time, screening based on the entire library greatly reduces screening costs and time costs
.

3.
How to optimize the lead compound?

Because lead compounds usually have some defects, such as insufficient activity, insufficient selectivity, unstable chemical structure, pharmacokinetics or greater toxicity, etc.
, it is necessary to carry out appropriate chemical modification of the lead compound to make it more ideal For drugs, this process is called lead compound optimization
.
Since the editor has recently "dead" drug candidates due to problems such as solubility and toxicity, seeing that its years of research and development have been ruined, I will explain these two aspects
.

In the process of lead compound structure optimization, proper solubility is crucial
.
Good water solubility can improve the drug-like properties of the compound, and improve the pharmacokinetic properties of the drug in the human body such as absorption, distribution, metabolism, and excretion
.
Therefore, paying attention to the structural modification of the water solubility of the compound will enable us to do more with less in the process of optimizing the structure of the lead compound
.
Chemical modification and improvement of the basic strategy theory soluble lead compound, including a salt, polar groups are introduced, reduced fat soluble conformation optimization, etc.
modified prodrugs
.
The improvement of fat solubility is mainly aimed at central nervous system drugs
.
In order to overcome the blood-brain barrier and achieve sufficient exposure in the central system, this is a key prerequisite for the success of central drug development.
In this way, we also need some strategies to increase the lipid solubility of drugs.
Commonly used optimization strategies include: transformation for passive diffusion~ Increase fat solubility, reduce hydrogen bond donors, simplify molecules, increase rigidity, reduce polar surface area, remove carboxyl groups, and prodrug strategies, etc.
; modification for active transport ~ modification of compounds as substrates for active transporters; for efflux rate Higher compounds ~ avoid groups that are easily recognized by efflux transporters
.

In view of the potential toxicity risk of the vigilant structure, in the development process of the lead compound, structural optimization of the vigilant structure is an effective method to reduce the potential toxicity of the lead compound
.
There are two main ideas: one idea is to remove the vigilant structure in the drug
.
If the vigilance structure is not the pharmacophore of a drug, removing the vigilance structure can both simplify the molecule and reduce the toxicity; if the vigilance structure is essential for activity or the necessary connecting fragments, you can consider using the principle of bioelectronic isostere The easily metabolized vigilant structure is replaced with a weak metabolizing group for bio-isosteres to achieve the purpose of reducing toxicity
.
Another way of thinking is to modify the vigilance structure by introducing blunt groups to block metabolic sites or introducing more metabolizable groups to change the original metabolic pathway of the compound so that it cannot produce active metabolites and block its toxicity.
Metabolic pathways
.
Specifically, the transformation of strategies to optimize the structure of alert include: metabolic closed sites, changes in metabolic pathways, reduced reactivity, bioisosteres and prodrug principle and so on
.
Such as phenacetin changed to acetaminophen, troglitazone changed to rosiglitazone and pioglitazone and so on
.

4.
Some feelings

Remember that when I first came into contact with the concept of "compounds", the first thing I looked at was the biological activity corresponding to the structure, and my eyes were only on those structures with activity at the nM level.
With the tracking of clinical drug candidates and the research of marketed drugs It was found that the compound with the strongest activity may not necessarily be the first of its kind to be marketed, and further study and understanding have also made it clear that the "drugability" of the compound is far more important than the "activity", and this " The discipline and knowledge involved in the technical aspects of "pharmaceutical properties" is "that is quite extensive"
.
In addition, through learning and thinking about innovative drugs in recent years, the editor has become more and more aware that the complementarity and complement of different disciplines and different methods are becoming more and more important in the process of searching for lead compounds.
Roles, using a variety of methods, comprehensive analysis and evaluation from multiple aspects, often can not only get a relatively good lead compound, but also does not lose other beneficial biological activity characteristics
.
Nowadays, new drug research and development are no longer alone.
Team collaboration and team philosophy have been popularized in many pharmaceutical companies.
Only multidisciplinary cooperation and collaboration can ensure that drug development is under the escort of subjective and objective escorts to find the last.
lucky!

references

1.
Song HP, Wu SQ, Qi LW, et al.
A strategy for screening active?lead?compounds?and functional?compound?combinations from herbal medicines based on pharmacophore filtering and knockout/ knockin chromatography[J].
Journal of Chromatography A , 2016, 1456(22), 176-186.

2.
Ayati A, Emami S, Asadipour A, et al.
Recent applications of 1,3-thiazole core structure in the identification of new?lead?compounds?and drug discovery[J].
European Journal of Medicinal Chemistry, 2015, 97 (5), 699-718.

3.
Marasco D.
7-Synthetic Peptide Libraries: Chemical Diversity to Reach?Lead?Compounds[J].
Current Developments in Biotechnology and Bioengineering, 2017, 143-159.

4.
Guo Zongru
.
On the optimization of lead compounds and the determination of candidate drugs [R]
.
Academic Annual Meeting of Chinese Pharmaceutical Association, 2006.

5.
Tang Yun, Chen Kaixian, Ji Ruyun
.
Reasonable drug design research [J]
.
Progress in Pharmacy, 1994, 4:193-198.

6.
Gao Yan, Jia Xin, Guo Donggui
.
Research progress in obtaining methods of lead compounds[J]
.
Science and Technology Information, 2009, 2: 9-11.

7.
Wang Jiang, Liu Hong
.
Lead compound structure optimization strategy [R]
.
The Journal of Pharmacy Frontier Forum and the Meeting of the Chinese Medicine and Natural Medicine Professional Committee of the Chinese Pharmaceutical Association, 2015.