Talking about the drug-like and pharmaceutical properties of innovative drugs

Many years ago, the US FDA has counted that the efficiency of innovative drug development in the United States is roughly, "250 of 10,000 compounds can enter preclinical research, of which only 5 can enter clinical research, and in the end only 1 can be obtained.
"Listing", the overall success efficiency is "one in 10,000"
.
The reason why new drug R&D has such a high-risk feature is inseparable from the R&D process and the ever-increasing high requirements of the drug review department for drugs
.
From basic research to drug discovery, from drug discovery to entering the development phase, to the later stage of registration and review, and production and marketing, every process of the evolution of a compound to a drug is faced with numerous difficulties.
To overcome these difficulties, the initial stage Research work is particularly important.
After all, a good start is half the battle
.
Here, I have to deal with the issue of "drug-like properties and drug-like properties"! PART 0 1.
Introduction to the new drug R&D process Generally, new drug R&D has to go through the following process: discovery of functional genomes, disease pathology, etc.
Provide new targets and theories for new drug discovery as the upstream basic research stage; use new targets and theories to combine Existing technologies form patents and candidate compounds are the new drug discovery stage; pre-clinical comprehensive evaluation, clinical evaluation, and industrialization process research for candidate drugs are the new drug development stage; registration on the basis of the foregoing is the listing stage
.
In the end, for the benefits of sales, a professional sales team is needed.
After all, there are countless cases of good products being sold out! PART 0 2.
Drug-like properties-the choice of lead compounds! The so-called drug-like properties represent the basic characteristics of an ideal drug.
It is the physical and chemical properties (such as relative molecular mass, lipid-water partition coefficient, etc.
) and structural characteristics (such as ring structure, number of rotatable bonds, etc.
) exhibited by the drug.
)'S comprehensive reflection
.
The structure and physicochemical properties exhibited by the drug-like compounds must have a good correlation with the pharmacokinetic parameters in the body, which can be regarded as the most basic requirements for the sprouts or lead compounds! The method of judging drug-like properties can be roughly divided into three categories: based on physical and chemical properties, based on specific structural fragments, and based on discriminant analysis models
.
The distribution of drug molecules in the chemical space is not uniform, but concentrated in a relatively small area
.
A large number of studies have been conducted on the physicochemical properties related to pharmacokinetic properties and bioavailability, and these properties are used as evaluation indicators for drug-like properties
.
Regarding drug-like properties, I have to mention the popular Lipinski "five rules for drug-like drugs", namely: relative molecular mass <500, the number of hydrogen bond donors <5, the number of hydrogen bond acceptors <10, and Log P <5, if If a compound violates the rules of 2 or more in Ro5, it is less likely to become an oral drug
.
The five rules here means that each parameter in this set of rules is a multiple of 5, not five rules
.
Ro5 is widely used in the preliminary screening of compound libraries in order to eliminate molecules that are not suitable for drugs, narrow the scope of screening and reduce the cost of drug development.
It is currently the most widely used drug-like evaluation index
.
The physical and chemical properties of drugs are concentrated in a certain range, and there are also such rules in the structure of drug molecules
.
Some structural fragments are related to the toxicity or side effects of the compound, and some can show good pharmacological activity and pharmacokinetic properties (such as the content of aromatic amines, aromatic nitro groups, sulfur atoms, and halogens have a positive effect on the druggability of the compound) Therefore, summarizing the laws of drug structure and specific structural features can also guide the evaluation and optimization of combinatorial compound libraries
.
In recent years, with the rapid development of computer technology and the rise of omics research, people’s research on drug-like structural fragments has risen to the level of fragmentomics (scaffoldomics or fragmentomics), and a Fragment-based Drug Design (Fragment-based Drug Design) has been proposed.
Design, FBDD) Theory and Method
.
According to the physical and chemical properties and structural characteristics of the compound, using various computer learning methods, through training on drugs and non-drug compounds, it is also possible to establish a calculation model for automatically classifying drug compounds and non-drug compounds.
In this way, it will greatly improve The study of drug-like properties
.
PART 0 3.
Drug-preparedness-the choice of drug candidates! The so-called "pharmaceutical properties" refers to the ADME properties and safety properties sufficient to enable the active compound to enter clinical phase I trials, including suitable physical chemistry, biochemistry, pharmacokinetics, safety, and structural novelty properties
.
In short, druggability is an essential feature for candidate drugs and even drugs
.
The appraisal of drug candidates belongs to the drug development stage, which includes three aspects: pre-clinical comprehensive evaluation, clinical evaluation and industrialization research
.
The bottleneck of the low efficiency of new drug creation in China at this stage is undoubtedly the comprehensive evaluation of preclinical drug properties
.
Pre-clinical comprehensive evaluation is the common pathway for all drug development.
All drugs must go through this stage of work to determine safety, effectiveness, and controllable quality.
It can be divided into biological evaluation and pharmaceutical evaluation
.
Biological evaluation is mainly to clarify the efficacy, mechanism of action, toxicological response, pharmacokinetic characteristics and drug interactions of candidate drugs
.
The key to drug efficacy evaluation is to use reasonable animal disease models for evaluation based on future clinical indications; toxicology evaluation needs to strictly follow GLP requirements, discover possible toxic effects and toxic target organs of candidate drugs, and provide possible clinical adverse reactions Reference direction; pharmacokinetic evaluation is to provide reference data for clinical dosing programs; the purpose of pharmacy evaluation is to determine the appropriate preparation process route and establish reliable, stable and simple quality control standards and methods, especially considering the feasibility of future industrialization Sex
.
Clinical evaluation is the decisive stage of the development of new drugs.
Major hospitals carry out it in accordance with GCP requirements.
New drug development units must have corresponding clinical professionals to implement the development intentions and cannot rely solely on clinical units passively
.
The rationality of the research plan, the completeness, objectivity, and standardization of the research data are the core content of the evaluation
.
Do not give up easily for results that are inconsistent with the expected goals.
Careful analysis should be carried out
.
Unexpected results may be found .
Industrialization research is to conduct research on the large-scale production process of new drugs with the goals of environmental protection, cost, and quality.
The goals of industrialization should run through the entire process of new drug development.
This type of work has become increasingly popular in China’s current new drug R&D units.
Pay attention
.
PART 0 4.
Summary and thoughts When we are making innovative drugs, the importance of the activity problem goes without saying
.
Not to mention mM-level compounds, μM-level compounds are usually passed by us, but when we really get nM-level compounds, we really can’t be happy too early, because it needs to be solid before becoming a real drug.
So many experiences
.
Seriously consider, simulate, and test its "drug-like properties" in the drug discovery stage, build a solid foundation, and then transfer to the "drug properties" in the drug development stage, which will greatly improve the efficiency of new drug discovery and creation, and minimize and avoid drug discovery.
It is a pity that a drug candidate stops in the clinic due to an "emergency situation"! References: 1.
Sugiyama Y.
Druggability: selecting optimized drug candidates [J].
Drug Discovery Today, 2005.
2.
Harry J, Tom LB, David B A.
Flexibility and small pockets at proteineprotein interfaces: New insights into druggability [J ].
Progress in Biophysics and Molecular Biology, 2015.
3.
Hussein HA, Geneix C, Petitjean M, et al.
Global vision of druggability issues: applications and perspectives [J].
Drug Discovery Today, 2016.
4.
Li Xiao, Kong Dexin .
Prediction methods for the drug-readiness of compounds[J].
Computers and Applied Chemistry, 2012.
5.
Xu Weiren, Tang Lida.
Strengthen the comprehensive evaluation of drug-ready properties to improve the efficiency of new drug creation in my country[J].
China Medical Technology Economics and Management, 2007.