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Screening and optimization of lead compounds for new drug development

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Lead compound is a compound with biological activity and unique chemical structure. Lead compound optimization is the process of transforming active compounds into drugs through structural transformation, and evolving non-drugs into candidate drugs or new drugs. It is an important content of new drug development. In the process of new drug research, a large number of lead compounds are obtained through compound activity screening. With the continuous development of screening technology, especially the continuous maturity of high-throughput screening technology, the probability of discovering compounds has been greatly increased. The screening of lead compounds includes the screening of non-antibacterial activity lead compounds, the screening of anticancer activity natural lead compounds, and the screening of antioxidant activity lead compounds.

The purpose of lead compound optimization is to determine the structure of candidate drugs and enter the new drug development stage. It marks the completion of the cyclic operation and reciprocating feedback of molecular design, chemical synthesis, biological evaluation of the optimization process, and entering the new drug development stage. Medicilon, which ranks high in China’s GLP organization, can provide customers with drug R&D services covering various targets and disease fields, including hit compound discovery, target verification, lead compound optimization, and preclinical drug candidate selection.

Lead compound activity screening

(1) Screening non-antibacterial activity lead compounds by compound activity

Modern biotechnology, especially the progress of molecular biology research, has shown the superiority of using recombinant microbial technology to screen non-antibacterial activity lead compounds. The method simplifies the analysis and detection process, reduces the occurrence of false positive results, and is suitable for high-throughput screening systems. At present, many effective lead compound screening models have been established using this technology. The target screening system based on recombinant microbial technology is to clone the gene encoding the foreign target protein, transfer it to the host (microorganism) and express it, and then use classical methods to evaluate the characteristics (such as survival) of the recombinant microorganism.


(2) Screening natural lead compounds with anti-cancer activity through compound activity screening

With the in-depth study of tumorigenesis mechanism, people have designed some methods to screen anti-cancer drugs using new mechanisms of action by taking relevant enzymes and receptors in the process of tumorigenesis and development as targets. For example, methods such as inhibition of DNA topoisomerase, anti-mitosis, inhibition of growth regulation and signal transduction pathways, calcium ion channel blockers, etc. These methods are particularly suitable for the follow-up separation and screening of natural anti-cancer lead compounds. Some new natural lead compounds with potential anti-cancer activity have been screened using these methods.

(3) Compound activity screening technology to screen lead compounds for antioxidant activity

Antioxidant active lead compounds are generally used in the treatment of cardiovascular diseases. For example, using a multi-target mechanism, a series of new-structured staghorn ketal compounds isolated from South China Sea fungi, these compounds can inhibit the contraction of the vascular ring caused by phenylephrine, and the nitric oxide synthase inhibitor L- The combination of NAME can significantly weaken its vasodilation effect. Moreover, it can significantly inhibit the hydrogen peroxide-induced cell apoptosis, mitochondrial membrane potential drop and the release of cytochrome C, which also suggests that the compound has an intracellular antioxidant effect.

Lead compounds often cannot be developed as new drugs due to their low activity, low selectivity, or poor pharmacokinetic properties. Chemical modification of the lead compound and further optimization can make it develop into an ideal drug.

The purpose of lead compound optimization

(1) Make the lead compound an acceptable new chemical entity

Applying the principles and methods of medicinal chemistry, through design and synthesis, the clinical requirements for drug quality are integrated and reflected in structural optimization and transformation, so that the safety, pharmacodynamics, pharmacokinetics, metabolic stability and pharmacy of the drug ( Physical chemistry) and other properties are harmoniously unified in the molecular structure, becoming a new chemical entity with therapeutic value and acceptable to the human body. 

(2) Make lead compounds into drug candidates with development prospects 

From a material point of view, the process of new drug creation is to select seed compounds from a large number of compounds, and evolve them into leads through molecular docking and drug screening, and then through multiple rounds of docking and optimization into candidate drugs with development prospects; from a biological point of view, This is an experimental process in which the chemical structure and biological properties of substances are constantly fed back and intertwined.

(3) Make the lead compound a knowledge value chain for creating new drugs

From a computer perspective, it is the process of kneading the conformations of small drug molecules and biological macromolecules into a complex in a graphical manner according to the principle of geometric complementarity, forming a knowledge value chain for the creation of new drugs. In this value chain, each node or link embodies the value of knowledge, technology and input, and the value content of the latter links includes the value covered by the previous efforts, so the value content is higher in the later period. If the development of a new drug fails in the later stage, it will cause great losses. Therefore, in the optimization stage, the activity and various properties and factors that affect the druggability should be investigated and determined.

In the process of new drug development, compounds with obvious defects and no prospects for drug development should be discarded as soon as possible. The results of various in vivo and in vitro tests are fed back to the new round of design and synthesis in real time, until the various properties of the compound are optimally matched, and the candidate drug can be determined.

Before optimizing the lead compound, it is necessary to study the properties of the lead compound and understand the corresponding mechanism of action, and clearly know the structure, physicochemical properties, pharmacological activity, side effects, toxicity, and metabolic processes in the body and the specific metabolites of the lead compound. Information; then you need to determine the optimization goal and formulate a concise optimization goal. Study the shortcomings of the lead compound first, and then optimize and modify it.

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