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How do synthetic or medicinal chemists design, synthesize and optimize thesynthesis of pharmacologically active compound/lead/drug based on the discovery from natural products?

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How do synthetic or medicinal chemists design, synthesize and optimize thesynthesis of pharmacologically active compound/lead/drug based on the discovery from natural products?

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Hi, I’m Nur Ishaireen.

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

1. Dzobo K. The Role of Natural Products as Sources of Therapeutic Agents for Innovative Drug Discovery. Comprehensive Pharmacology. 2022:408–22. doi: 10.1016/B978-0-12-820472-6.00041-4.

2. Xiao Z, Morris-Natschke SL, Lee KH. Strategies for the Optimization of Natural Leads to Anticancer Drugs or Drug Candidates. Med Res Rev. 2016 Jan;36(1):32-91. doi: 10.1002/med.21377.

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How do synthetic or medicinal chemist design, synthesis and optimize the synthesis of pharmacologically active compound/ lead/ drug/ based on the discovery from natural products ?

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How do synthetic or medicinal chemist design, synthesis and optimize the synthesis of pharmacologically active compound/ lead/ drug/ based on the discovery from natural products ?

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Hi, I'm Ainnur Rusydina

Natural products is important role in drug discovery as a treatment for cancer, infectious diseases, therapeutic areas, including cardiovascular diseases ( statins) and multiple sclerosis ( fingolimod ). Plant based medicines are still being used to treat many pathological conditions or are used as alternatives to modern medicines. In most cases, these natural products or plant-based medicines are used in an un-purified state as extracts. Advances in analytical processes make drug discovery a multi-dimensional process involving computational designing and testing and eventual laboratory screening of potential drug candidates. Lead compounds will then be evaluated for safety, pharmacokinetics and efficacy. The process begins with extraction of NPs from organisms such as bacteria. the next step is its (often multiple) consecutive bioactivity-guided fractionation until the pure bioactive compounds are isolated. Finally, at the last stage, when bioactive compounds are identified by phenotypic assays, significant time and effort are typically needed to identify the affected molecular targets. 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 use of bioinformatics and computation means that drug discovery can be a fast and efficient process and enable the use of natural products structures to obtain novel drugs. For example, medium-throughput to high-throughput robotic screening in specialized assays has become standard in the pharmaceutical industry.  The breadth of other applications of automated systems extends from decision-support systems, to computational molecular design to fully fledged robotic synthesis and hit finding.  Prominent examples include traditional rule-based and model-based approaches (for example, the archetypal DENDRAL system for analysing mass spectra, LHASA software for synthesis planning and various in-house tools for accessing and analysing chemical and biological data similar to Amgen's AADAPT system), various software tools for de novo molecular design and prototypical robotic systems such as ADAM and EVE for automated target and hit finding. NPs are structurally ‘optimized’ by evolution to serve particular biological functions1, including the regulation of endogenous defence mechanisms and the interaction (often competition) with other organisms, which explains their high relevance for infectious diseases and cancer.

References

1) Schneider, G. Automating drug discovery. Nat Rev Drug Discov 17, 97–113 (2018). https://doi.org/10.1038/nrd.2017.232.

2) Atanasov, A.G., Zotchev, S.B., Dirsch, V.M. et al. Natural products in drug discovery: advances and opportunities. Nat Rev Drug Discov 20, 200–216 (2021). https://doi.org/10.1038/s41573-020-00114-z.

3) Dzobo K. The Role of Natural Products as Sources of Therapeutic Agents for Innovative Drug Discovery. Comprehensive Pharmacology. 2022:408–22. doi: 10.1016/B978-0-12-820472-6.00041-4. Epub 2022 Jun 9. PMCID: PMC8016209.

4) Katiyar C, Gupta A, Kanjilal S, Katiyar S. Drug discovery from plant sources: An integrated approach. Ayu. 2012 Jan;33(1):10-9. doi: 10.4103/0974-8520.100295. PMID: 23049178; PMCID: PMC3456845.

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How do synthetic or medical chemists design, synthesize and optimize the synthesis of pharmacological  active compound/ lead/ drug based on the discovery from natural products?

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How do synthetic or medical chemists design, synthesize and optimize the synthesis of pharmacological  active compound/ lead/ drug based on the discovery from natural products?

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Hello my name is Sanita

Natural products (NPs) have played a key role in drug discovery, especially for cancer and infectious diseases but also in other therapeutic areas, including cardiovascular diseases. Nevertheless, natural products also present challenges for drug discovery, such as technical barriers to screening, isolation, characterization and optimization, which contributed to a decline in their pursuit by the pharmaceutical industry from the 1990s onwards.

Medicinal chemists use synthetic procedures to create compounds for new medicines, and to re-synthesize screening hits for biological evaluation. Medicinal chemists usually synthesize compounds using legacy reactions that generate structurally similar compounds, however change on the horizon.

Medicinal chemists specialise in compound design, where they help to balance and combine the competing parameters of structure and biological function. Compound quality is an increasingly critical area of concern across pharma, where diminishing success rates of clinical compounds are driving attrition in development.

In optimization of drug or lead, it is happen after modifying the lead compound, the next step is to study the pharmacodynamics (how the drug can affect the body) and pharmacokinetics (how the body might affect the drug). Although there is no foolproof way to predict these properties (hence the need for clinical trials!), we must still attempt to make educated guesses based on the data.

References
1) Atanasov, A.G., Zotchev, S.B., Dirsch, V.M. et al. Natural products in drug discovery: advances and opportunities. Nat Rev Drug Discov 20, 200–216 (2021). https://doi.org/10.1038/s41573-020-00114-z
2) Behruz Sheikh. (2022, May 24). 4 Ways Medicinal Chemists Power Drug Discovery and Development. Retrieved from https://www.srgtalent.com/blog/4-ways-medicinal-chemists-power-drug-discovery-and-development
3) FTLOSCIENCES. (2022, November 23). Medicinal Chemistry: Lead Modification and Optimization. Retrieved from https://ftloscience.com/medicinal-chemistry-lead-modification-optimization/

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How do synthetic or medicinal chemist design, synthesize and optimize the synthesis of pharmacologically active compound/lead/drug based on the discovery from natural products

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How do synthetic or medicinal chemist design, synthesize and optimize the synthesis of pharmacologically active compound/lead/drug based on the discovery from natural products

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Hi, I am Wong Chee Lok

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.

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How do synthetic or medicinal chemists design, synthesize and optimize the synthesis of pharmacologically active compound/lead/drug based on the discovery from natural products?

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How do synthetic or medicinal chemists design, synthesize and optimize the synthesis of pharmacologically active compound/lead/drug based on the discovery from natural products?

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Hi, I am Yap Voon Sing

Drug discovery is the process through which potential new therapeutic entities are identified, using a combination of computational, experimental, translational, and clinical models.
On the other hand, drug design is the inventive process of finding new medications based on the knowledge of a biological target.In the most basic sense, drug design involves the design of molecules that are complementary in shape and charge to the molecular target with which they interact and bind. Drug design frequently but not necessarily relies on computer modeling techniques and bioinformatics approaches in the big data era.The main step in a successful drug discovery pipeline is the identification of small potent compounds that selectively bind to the target of interest with high affinity. By carrying out various studies, we are able to design a drug high activity and target selectivity.
After the drug has been designed, Medicines drug optimisation has been carried out.In this process, the medicines are made sure being delivered, thus ensuring they are clinically-effective and cost-effective. It is about ensuring people get the right choice of medicines, at the right time, and are engaged in the process by their clinical team. It is important to carry out drug optimisation as it helps to ensure the drug safety and reduce the wastage of drug.

Reference
1) Drug Design and Discovery: Principles and Applications
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6155886/

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

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How do synthetic or medicinal chemists design, synthesize and optimize the synthesis of pharmacologically active compound/lead/drug based on the discovery from natural products?

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How do synthetic or medicinal chemists design, synthesize and optimize the synthesis of pharmacologically active compound/lead/drug based on the discovery from natural products?

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Hi my name is Wong Yong Jie.

Drug discovery
Traditional Chinese medicines are used much more frequently these days to fend off chronic illnesses. These products, which are included in prescription drug regimens, may enhance the therapeutic effects of traditional therapy. Endogenous natural materials with a variety of medicinal characteristics were the main source of medications in prehistoric society. Electrophysiological tests were used to evaluate a large number of compounds before choosing the natural products.
Over time it has been discovered that the synergistic effects of the different compounds within these extracts is the reason why they have healing power. The purification of plants compounds sometimes leads to loss of healing power and loose of therapeutic efficacy.

Drug design
The inventive method of developing novel drugs based on an understanding of a biological target is known as drug design. Designing molecules that are complementary in shape and charge to the molecular target with which they interact and bind is the most fundamental aspect of medication development. In the big data era, drug design usually but not always relies on bioinformatics methods and computer modelling techniques.

Drug optimisation
Medicines optimisation examines the value that medications provide, ensuring that they are both clinically and financially effective. It involves making sure patients receive the appropriate medications at the appropriate time and are involved in the process by their healthcare team.  The purpose of medication optimisation is to assist patients in achieving better results, taking their medications appropriately, avoiding taking superfluous medications, reducing medication waste, and enhancing medication safety.

Reference
1. The Role of Natural Products as Sources of Therapeutic Agents for Innovative Drug Discovery

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/

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How do synthetic or medicinal chemists design, synthesize and optimize the synthesis of pharmacologically active compound/lead/drug based on the discovery from natural products?

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How do synthetic or medicinal chemists design, synthesize and optimize the synthesis of pharmacologically active compound/lead/drug based on the discovery from natural products?

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Hi, I am Cho Han Xian.
Drug Discovery

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

https://www.chemeurope.com/en/encyclopedia/Total_synthesis.html

https://www.chemeurope.com/en/encyclopedia/Semisynthesis.html

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).