A lead compound is a compound with a unique structure with certain activity or potential activity, which is the starting point of modern new drug research. It cannot be directly developed as a new drug because of the drawbacks such as too little activity, low selectivity, poor pharmacokinetic properties or high toxicity, etc. However, a series of structural modifications or modifications can be carried out on the basis of the structure of the compound to obtain a new drug that meets the therapeutic requirements. With the increasing development of science and technology, there are more and more methods to find and obtain lead compounds, which are summarized as follows:
1 Extensive screening and accidental discovery
1) Extensive screening
Extensive screening is the traditional method of obtaining lead compounds, which is the process of obtaining biologically active substances on the basis of numerous studies. The initial search for new drugs and the acquisition of lead compounds were carried out by this method. Early screening was characterized by the extraction of active ingredients from natural medicinal plants. With the development of the chemical industry, especially dye chemistry, the increasing progress of chemical methods and the rising medical needs, people were prompted to put many chemical industrial products, especially dye intermediates for large-scale and extensive pharmacological screening, and a large number of chemicals with medical value were discovered. For example, the antipyretic and analgesic drug finasteride and the precursors of acetaminophen, aniline and acetanilide, were discovered from the screening of dye intermediates.
2) Accidental discovery
Accidental discovery is also one of the ways to obtain lead compounds and drugs. There are many lead compounds and drugs discovered by this method, such as the antibacterial drug penicillin, the antitumor drug cisplatin, etc. were obtained by chance, and people subsequently carried out conformational studies on them to develop a series of new drugs.
2 Mechanism-based drug design
According to the pathogenesis of the disease and the mechanism of drug action, the design of chemical drugs for its key links and restrictive steps, while taking into account the transport and metabolism of drugs in the body, is called mechanism-based drug design. It is another shortcut to the discovery of lead compounds. The human organism is composed of cells, whose activity is controlled by external signals, which are transmitted to the inside of the cell, causing a series of intracellular responses. Once the signaling pathway is different, it will lead to the imbalance of balance, which is the basis of the disease mechanism. On this basis, the mechanism of action of signaling molecules can be investigated to discover and obtain new lead compounds. In addition, new lead compounds can be discovered and obtained by studying the mechanism of action of bioactive peptides, neurotransmitters such as acetylcholine and 5-hydroxytryptamine, as well as active substances secreted by endocrine glands in the organism.
3 Obtaining from existing drugs
Some of the existing drugs can be selected as lead compounds and further optimized to obtain new drugs. New lead compounds can also be obtained from existing drugs in the following ways. The main ones include:
1) Discovery of new lead compounds from drug side effects
In drug research, new drugs can often be found from the toxic side effects of known drugs, or new drugs can be obtained by separating toxic side effects from therapeutic effects. In some cases, the toxic side effects of a drug may have a therapeutic effect on another disease.
2) Obtaining new lead compounds through compound metabolism research
Through the process of metabolism in the body, drugs may be activated or inactivated, or even transformed into toxic compounds. In drug research, it is possible to select the activated form, or to consider the structure that can avoid metabolic inactivation or toxicity as the lead compound of a drug. Using this type of lead compounds, there is a higher possibility of getting excellent drugs, or even directly getting better drugs than the original ones.
3) Using existing breakthrough drugs as new lead compounds
In recent years, with the understanding of physiological and biochemical mechanisms, we have obtained some breakthrough drugs for the treatment of diseases, which are called prodrugs. A large number of “me-too” drugs have been obtained through bioelectronics and other methods using prototypic drugs as lead compounds.
4) Search for new lead compounds through metabolites
The study of animal excretions and secretions is also a way to obtain new lead compounds. For example, antitumor ketone A10 is a natural small molecule anticancer active substance isolated from human blood and urine.
4 Access through compound libraries
Large drug research and development organizations around the world have their own stocks of isolated, synthesized or collected compounds to form compound libraries. These include natural product libraries obtained from natural product extraction and isolation and structure determination, large-capacity chemical molecule libraries formed by chemical synthesis, especially by combinatorial chemical technology, and genetic engineering libraries established through protein expression. They all exist to serve the discovery of lead compounds.
5 High-throughput virtual screening
High-throughput virtual screening is a method of searching for possible active compounds in compound databases by using the powerful computational ability of computers and employing three-dimensional pharmacophore modeling or molecular docking.
1) Pharmacophore-based database searching
Pharmacodynamic groups are usually those atoms or functional groups that can form hydrogen bonding interactions, electrostatic interactions, van der Waals interactions, and hydrophobic bonding interactions with receptor binding sites. The pharmacophore modeling approach is an important indirect drug design method for lead compound discovery. The distribution of pharmacophore and pharmacophore elements in space (distance limitation) constitutes a three-dimensional pharmacophore. Three-dimensional pharmacophore models are generally established by performing structure-activity relationship analysis on a group of biologically active compounds to identify their common characteristic structures. In addition, 3D pharmacophore models can also be obtained by analyzing the crystal structure of the active compound in complex with its target. The 3D pharmacophore search is relatively fast, and preprocessing the compound database before molecular docking can improve the discovery of small molecules that are active on the target biomolecules.
2) Virtual screening based on molecular docking
Molecular docking is a technique in which two or more molecular models in a molecular simulation environment form an optimal combination by matching geometry, chemical environment and energy. Virtual screening based on molecular docking requires three-dimensional structural information of target biomolecules and small molecule compounds. First of all, it is necessary to establish a large number of compounds (e.g. dozens or even hundreds of compounds) of the three-dimensional structure of the database, and then the molecules in the database one by one with the target molecule “docking”, through the continuous optimization of the position of small molecule compounds (orientation) and molecular flexible bond dihedral angle (conformation), to find the best conformation of the small molecule compounds and target macromolecules. By continuously optimizing the position (orientation) of the small molecule compound and the dihedral angle (conformation) of the flexible bond within the molecule, we search for the best conformation of the small molecule compound to interact with the target macromolecule, and calculate its interaction and binding energy. As long as the compounds in the database have a sufficiently large molecular diversity, it is possible to search for the ideal molecular structure from the library.
In conclusion, when searching for lead compounds, different disciplines and methods complement and supplement each other. Only by applying multiple methods and comprehensively analyzing and evaluating from various aspects can we obtain better lead compounds without losing other beneficial bioactive substances.
PONY Bio-pharmaceuticals has two biopharmaceutical bases in Shanghai and Beijing, and a production base in Hubei, which is a comprehensive technical platform integrating drug design, drug synthesis, process development, drug production, drug activity screening, formulation research, pharmacodynamic evaluation, pharmacokinetic evaluation, toxicological evaluation and new drug registration, and has the qualification of CMA and CNAS, and is implemented in accordance with GMP and GLP. It is implemented in accordance with GMP and GLP, and has been recognized by domestic and international drug regulatory authorities. The core R&D personnel of the laboratory are all returned PhDs with years of experience in R&D in large international pharmaceutical companies and CDMOs and senior professionals in the domestic drug field.
