The drug discovery from natural products involves the identification of new active compounds which are usually called as hits. These hits are originated from natural sources such as plants, animals, and microorganisms and they are found to have therapeutic effects that can treat diseases. The chemists will do screening (ex: High Throughput Screening – HTS) to identify and select the active compounds that exhibit the desired biological properties. Then, they will isolate and purify the compounds from natural sources. 

Drug Design and Synthesis

Drug design is an inventive effort of designing a suitable lead molecule to make it more active and safer with less toxicity than the original lead molecule that may properly bind with its specific receptor sites to produce a certain pharmacological effect. Medicinal chemists have to find new medications based on the knowledge of a biological target to ensure the drug molecule is suitable for binding with particular receptor sites. Drug synthesis can be classified into three types which are total synthesis, semi-synthesis, and biosynthesis. Total synthesis refers to synthesizing complex molecules (natural products) from simple starting materials through many steps. Semi-synthesis involves the use of natural sources as starting materials to form new compounds with different chemical and medicinal properties. Biosynthesis is a process where the substrates are converted into more complex compounds in living organisms and it is catalyzed by enzymes. 

Drug Optimization

Most hit compounds that have been extracted are not selective enough for their target molecule.  The hit-to-lead optimization is required in order to increase their selectivity and affinity. Therefore, medicinal chemists alter the compounds' structures according to predicted structure-activity relationships (SAR). If the alterations improve selectivity and affinity, the lead compounds may be able to move onto further optimization of other pharmaceutical properties. The optimization will focus on improving the biological properties of the pharmacophore which helps to increase the potency, selectivity, pharmacokinetics and pharmacodynamics properties and reduce the toxicity. If the optimization is successful, lead compounds can continue to proceed with the drug development process, where they become potential drug candidates.

 

References:

1)     Cancer Quest – Drug Development and Discovery

https://www.cancerquest.org/patients/discovery-and-development-drugs#:~:text=In%20natural%20drug%20discovery%2C%20the,from%20smaller%20chemical%20building%20blocks.

2)     Chemeurope.com – Total Synthesis and Semi-synthesis 

3)     PharmaEducation – Difference between Drug Design and Drug Development

https://pharmaeducation.net/difference-between-drug-design-and-drug-development/#:~:text=Drug%20design%20may%20take%200,1%20year%20for%20regulatory%20approval).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8016209/#:~:text=Many%20other%20drugs%20were%20discovered,extracts%20actually%20has%20healing%20powers.

2.Importance of Natural Products in the Modern History

https://www.rroij.com/open-access/importance-of-natural-products-in-the-modern-history-.php?aid=52894#:~:text=These%20products%20may%20increase%20the,a%20main%20source%20of%20drugs.

2.Drug Design and Discovery: Principles and Applications
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6155886/#:~:text=Drug%20design%20is%20the%20inventive,knowledge%20of%20a%20biological%20target.

3.Medicines optimisation

https://www.england.nhs.uk/medicines-2/medicines-optimisation/

In drug discovery process, medicinal chemist will first start with the choice of a disease area and identify the specific molecular “drug target” to be selected. High throughput screening (HTS) will be applied for screening and identifying the potentially active compounds ( hits)  and the validated hits will further studied for the relationships between their chemical structure and the biological activity. In this stage, the molecular scaffold will be studied and identified which then leading to the drug design and synthesis. Medicinal chemists could synthesize the compound through total chemical synthesis, semi chemical synthesis or biosynthesis according to the conditions. In total synthesis, it is involved the complete synthesis of a complex molecule from simple precursors while in semi-synthesis, the chemical compounds which isolated from the natural source is used as the starting materials for synthesis of the compound. As for biosynthesis, it is the generation of macromolecules through enzymatic reactions such as cellular metabolism.  The compound can then be undergoing optimization in order to optimize the target interactions, chemical and metabolic activity, hydrophilic/hydrophobic balance as well as the pharmacokinetic properties through modifying the structure of the compound. 

 

Reference 

[1]       PharmaCentral, Materials and Knowledge Platform. (2021, October 22). Drug Discovery and Development: A Step by Step Guide. https://pharmacentral.com/learning-hub/technical-guides/drug-discovery-and-development-a-step-by-step-guide/

[2]       Nogrady, T., & Weaver, D. F. (2005b). Medicinal Chemistry: A Molecular and Biochemical Approach. Oxford University Press.

Natural products offer an opportunity to discover new compounds that can be converted into drugs given their chemical structure diversity. Drug discovery is now a multi-dimensional process that involves computational planning and testing as well as final laboratory screening of possible drug candidates thanks to advancements in analytical methods. The effectiveness, pharmacokinetics, and safety of the lead compounds will then be assessed. New technologies including Artificial Intelligence, better organ and tissue models such as organoids allow virtual screening, automation and high-throughput screening to be part of drug discovery.

The medicinal chemist played a crucial role in the early phases of drug discovery. They are trained to prepare new chemicals and with an acquired knowledge of the target disease and of competitive drug therapies, also have an important part in framing the hypothesis for the new drug project. The scientists also decide the current chemicals to screen for lead compounds as well as the screening hits that need to be re-synthesised for biological testing. The chemist is also responsible for the new substances' purification and proper characterisation. The chemist decides what analogous compounds should be produced or synthesized to explore the SARs for the structural family of compounds in an effort to maximize the desired activity when an in vitro 'HIT' is identified. 

Optimization of natural leads into drug candidates should not only address drug efficacy, but also improve absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles and chemical accessibility associated with the natural leads. Direct chemical modification of functional groups, structure-activity relationship-directed optimization, and pharmacophore-oriented molecular design based on natural templates are all examples of optimisation methodologies. Modern computer-aided drug design methods as well as fundamental medicinal chemistry principles can both be used to help with optimisation efforts.

References