Lecture Notes - lecture 3
Drug Development Process
Our company develops new drugs for Israeli startups, international companies, and both small organic molecules and biomolecules.
Start from a concept.
Proceed via drug development.
Advance drugs to clinical trials.
We work with numerous clients in the Israeli biomed industry and internationally and contribute to the successful biomed hub. Our company consists of 12 people, including chemists, analytical chemists, and biologists, and we provide formulation development, analytical support, and clinical development.
Key Concepts in the Lecture
Introduction to medicinal chemistry.
Basic concepts in drug discovery.
Basic concepts in drug delivery formulation, focusing on solubility improvement.
The global pharmaceutical market is expected to grow by 7% and reach by the end of 2025, driving job growth for qualified professionals. Becoming a medicinal chemist requires specialized training beyond synthetic organic chemistry, including a strong background in biochemistry, biology, critical thinking, and technical skills.
Medicinal Chemistry
Medicinal or pharmaceutical chemistry is a scientific discipline intersecting chemistry and pharmacy, involved with designing and developing drugs.
It includes identifying, synthesizing, and developing new chemical entities suitable for therapeutic use.
It also involves studying existing drugs, their biological properties, and quantitative structure-activity relationships (QSAR).
QSAR
Quantitative Structure-Activity Relationship: This term is important and will be discussed frequently during the lecture.
Medicinal chemistry is an interdisciplinary science that focuses on small organic molecules and peptides. Small organic molecules are roughly those with a molecular weight below daltons (some scientists consider it below daltons). This is a rough description of small organic molecules.
Introduction to Drug Discovery
In the past, most drug discoveries came from identifying active ingredients from natural traditional remedies or by serendipitous discovery.
Traditional remedies: Like Paciflora.
Serendipitous discovery: Discovering something unexpected while searching for something else (e.g., penicillin discovered by Fleming).
Many drugs on the market are natural product derivatives, where the natural product structures were improved using medicinal chemistry to achieve better efficiency, safety, and stability.
Today, with diseases controlled at the molecular level, more drugs are discovered by rational, computer-driven drug design.
Examples of Natural Products
Aspirin: Known from Hippocrates' time, extracted from willow tree, used for pain and fever reduction.
Penicillin: Antibiotic, life-saving drug, extracted from penicillium molds.
Paclitaxel: Essential drug for chemotherapy, extracted from Pacific Yew bark.
Several unnatural products were discovered and inspired by natural products. Captopril, used for rational design, was inspired by snake venom extract. Some sequences of peptides, phenylalanine, proline, were used as a module for side chain interaction, and by rational design, it was simplified into non-peptide inhibitors of captopril.
Other drugs were inspired by nature but modified into unnatural products. Ritonavir, an efficient anti-AIDS drug, was discovered and developed by structure-based design using the molecular structure of peptide and molecular biological crystallography.
Natural products serve as medicinal chemistry targets, and they can come from any kind of natural living organism, including plants, microorganisms, animals, or terrestrial and marine sources.
Generally, natural products are secondary metabolites, which are organic compounds not directly involved in normal growth, development, or reproduction of organisms. They are used for protection or other roles.
Pharmacological Activities
Several of these compounds show pharmacological activities and are helpful for the invention and discovery of active components, as they have been known for thousands of years.
Cannabinoids: Used by traditional medical doctors from medieval and ancient times.
Natural products show a wide variety of biological activities, such as anticancer, anti-AIDS, antiviral, and antifungal properties.
Natural Products in Drug Development
According to a review cited in the transcript, 872 drugs out of 1562 are either natural products or derived from them. The utilization of natural products and novel structures to discover and develop final drug entities is still alive and well. Approximately half of known drugs come from natural products or are inspired by their structures.
Example
In ovarian cancer, from 1940 to the end of 2014, about 175 small approved molecules were used, and about 50 of them were still natural products. Starting with a natural product is still a fruitful and needed niche, and scientists continue to learn about them.
Plant Sources of Natural Products
Paclitaxel: Extracted from the Pacific Yew, essential drug in anticancer cocktails (e.g., for breast cancer). It is toxic even to other cells but used a lot in cancer treatment and now produced by plant cell fermentation technology.
Digoxin: Cardiovascular drug from the cardioglycoside family and medication, isolated from the Foxglove plant.
Dactinomycin: Chemotherapy medication, initially found as an antibiotic but repurposed due to its chemotherapy function and used to treat a number of types of cancer.
Process of Extracting Natural Products
Raw materials: Dried plant materials, flowers, bark, etc., are dried and powdered (micronized).
Extraction: Utilizing simple extraction procedures with organic solvents of different polarities, water, or their mixture. Supercritical fluid extraction replaces traditional solvent extraction as more environmentally friendly.
Purification: Conducted by preparative planner chromatography techniques.
Raw materials undergo extraction and filtration to produce a crude extract, and several extraction cycles can be applied. The extract goes through preservation and enrichment to yield a clean extract. The clean extract, still a mixture of different compounds, can contain hundreds of compounds.
Clean Extract
This extract can be dried by rotor evaporation or concentrated by centrifuging and filtering. The science obtains an impure compound mix, which undergoes purification, filtration, crystallization, or liquid chromatography techniques. Through this chain of impure compound mixtures, a pure compound is obtained.
Each pure compound in the sequence undergoes structure elucidation and database search. This is how natural compounds enter the libraries of millions of compounds.
Further Development Steps for Active Natural Compounds
Isolate or synthesize a family of similar compounds.
Identify the pharmacophore of the natural product.
Run toxicity and availability studies on cell models.
Modify activities using molecular biology or medicinal chemistry tools.
Rational Drug Design
Rational drug design involves target identification and validation. There is an artificial barrier between natural and synthetic compounds, but they can be mixed in one library and go through rational drug design.
Biological Target
A biological target relates to any medical condition, disease, or need for improvement that needs to be fixed. It is anything within a living organism where another entity, like an endogenous ligand or drug, is directed or binds, resulting in a change of its behavior or function. Biological targets can be measured.
Proteins are the most common targets, including enzymes, cells, receptors, structural proteins, and regulatory factors such as protein kinases. Other targets under investigation include nucleic acids such as RNA, lipids, and carbohydrates.
The target can be as simple as high acidity in the stomach, where antacids are used to elevate pH via a simple chemical reaction. In this case, there is no need for an enzyme or protein target to cure a medical condition.
A good target needs to be efficient, safe, meet clinical and commercial needs, and, above all, be druggable. There are many orphan and uncured diseases for which people still suffer and die.
A druggable target is acceptable to the putative drug molecule, whether a small molecule or larger biologic, and upon binding, elicits a biological response that can be measured both in vitro and in vivo. In medicinal chemistry, the focus is predominantly on small molecules, rather than large peptides, RNA, or proteins.
Computer-Aided Drug Design (CADD)
Computer-aided drug designs are major tools in drug discovery and use computational methods to simulate drug-receptor interactions. They include structure-based drug design, ligand-based drug design, and heat-to-lead optimization, each of which will be elaborated on further.
Drug Discovery and Development
Drug discovery and development can be represented by a scheme where a library of compounds (synthesized or natural) interacts with a target. In this representation, the compound is like a key and the drug target is like a lock.
Agonist and Antagonist
Agonist: Activates the enzyme or peptide (e.g., some drugs activate immune response to fight cancer cells).
Antagonist: Blocks the receptor and prevents interaction with a poison molecule (e.g., atropine injection prevents acetylcholine from reacting with certain chemical gases).
Libraries of compounds undergo molecular docking stimulation versus drug targets in in vitro screening. Compounds either block or activate the drug targets, and in this way, hits are identified. Heat optimization leads to leads, and lead optimization then yields molecular leads, and after different stages like molecular dynamic simulation and energy calculation, candidates go into in vitro testing.
Thousands of tests are conducted in vitro, and then some leads go to in vivo testing and preclinical tests with animals before entering clinical trials to become real drugs.
Cost and Time of Drug Discovery
To bring a new drug to market can take to years and can cost . This is the reason new drugs are so costly.
The process might start from a million molecules from a library and go through high-throughput screening to discover approximately 250 compounds (hits). These compounds undergo optimization to roughly a hundred compounds (leads). At the ADMET stage, ADMET (absorption, distribution, metabolic expression, and toxicity) studies, which are big and important in preclinical and formulation discovery, are carried out.
Only about five compounds finish this stage. These five compounds go to clinical trials and formulation optimization, and finally, a single compound goes for FDA review.
Heat and Lead
Heat generation starts with millions of compounds coming from natural products, treatment-oriented synthesis, or even commercial collections. One strategy is repurposing drugs, where drugs like aspirin originally used for fever reduction are found to also work as a blood coagulation agent.
Finding a suitable heat requires heat validation and determining the molecular structure of the compound to place it in a library. This entire library is screened to identify hits. Full live libraries are used for primary essay identification.
Method for Heat Identification
Bioassay methods are used, involving fluorescence reporting of biological function to monitor biological events and signals in cells and tissues. All molecules are tested at the same concentration, often at . Hits represent approximately 0.1% to 1% of all high-throughput screening molecules.
Fluorescence is measured versus a control by assessing the slope, area under the curve, and intensity. Potential hits, showing about 50% activity versus control, pass as goal criteria; otherwise, they are not considered. Selected screened compounds are then run through secondary assays.
Secondary assays confirm heat via dose-response or concentration response testing, starting from and decreasing to 0.1-1 nanomolar to determine whether the candidate persists in its potency even at lower concentrations. These results should be repeatable at least three times for minimal statistical significance in the secondary confirmation.
Early-Stage Drug Discovery Cycle
Computer-aided drug design, high-throughput screening, or medicinal chemistry methods screen from a library, directing the library for primary and secondary assays. Numerous calculations are done and structure-activity relationship studies are used. This process can be iteratively repeated to go from hits to lead molecules.
Heat-to-Lead Optimization
Heat-to-lead optimization refines the heat structure to produce proprietary compounds having additional fireable properties, including functional activity in cells.
At this stage, computational science is not enough, and validation should be conducted in cell lines indicated for the target disease.
The lead should have potency. If a compound is potent enough, the problems of solubility, protein binding, pure pharmacokinetics, and toxicity diminish or disappear.
Example
A broad screen campaign to find an inhibitor against HIV protease revealed Coumarin types. When scientists replaced hydroxycoumarin ring with hydroxypyridium, the inhibition concentration needed decreased significantly, being a more effective drug candidate. Further modification of the molecule by adding carboxylamine functionality led to a different inhibition concentration. Tryptanavir possesses an inhibitory concentration of 50% at 8 picomolar, and 90% inhibition at 100 nanomolar, much more active than the starting molecules. This structure-based design leads to the creation of Aptivirus, a very efficient drug.
Lead Validation
The ability of chemical compounds to elicit some pharmacological therapeutic effect is related to its influence on various physical and chemical properties of the chemical substance. These properties can be calculated for each molecule, including size, solubility, hydrogen bonding, ionization, surface polarity, flexibility, and aromaticity.
The next stage is measuring these properties. These properties then define cell permeability, cell line activity, metabolic stability, plasma protein binding, plasma stability, P glycoprotein interaction or metabolism, and protein binding.
Late-stage physicochemical properties will influence ADMET (absorption, distribution, metabolism, excretion) and toxicity properties. Having suitable ADMET properties and suitable efficacy helps advance leads to real clinical candidates, and should be considered early.
Example of Physicochemical Properties
Size
Everyone knows what size is and it is calculated based on all atoms that are in molecules.
Solubility
Solubility is the maximum dissolved concentration under given solution conditions, presented as low as concentration measured in milligram per milliliter or microgram per milliliter. Solubility determines intestinal absorption and oral bioavailability and should have certain solubility to be soluble in gastrointestinal fluid because only soluble molecule is absorbed.
In low-solubility drugs, even with a very good heat that went through high-throughput screening, if there is an issue with low solubility, it should be addressed and a better drug candidate with better solubility or a formulation approach should be used.
Lipophilicity
The tendency of a compound to partition in nonpolar lipid metrics versus aqueous metrics is presented as log p. Log p and lipophilicity is measured in octane of water and miscible liquid extraction part of part.
U log p is a very important value for heat validation, and also it should be between 0 to 3. Values outside this range indicate that the molecule will not easily pass membrane to bloodstream.
Hydrogen bonding: there Should be optimal ratio between donors and acceptors because interactions with the target are through hydrogen bonding
Ionization: Most drugs are ionizable or neutral. If it is ionizable it's good you have more tools to optimize.
The rules from Lipinski, aspects, Pfizer and Takeda are evidence based an works well, but they are limited and should not be taken for granted. They work for better absorptions and permeations.
Three from 75 Rule (Pfizer and Takeda)
These rules are for reduced in vitro toxicity. Simple cut-off going on the lipophilicity between 1 to 2 3 zero to three
Why they are so important?
Because if you place some unsafe drug unproper in the market, and this drug was fined and withdrawn because of his fatality and some heart rate rising.
A chemical modification is to have new molecule because you need a new patent.
Solubility Improvement
In medicinal chemistry, organic chemistry work, group, you should still have in your minds that you you preservable pharmacophore and working with other mites and group improve molecule.
You have to work in in cell to achieve balance between all these properties that are important for lead
Metabolic stability is very important. If it going and metabolize quickly in the body
WHAT DOES IT MEAN METABOLISM?
Metabolism is generally what body do to a drug and metabolic unstable compound.Metabolic unstable compound is pure pk or bioavailability and metabolizm to take some advantage from your molecule and eliminate it from the body
Increase drug polarity to have it more soluble catalyse conjugation to polar group to allow easy extraction excreation.
It can't completely fight metabolism but you want to extend t t half at least to have some activity of that.
Example to improv metabolic stability via star drop software
You it's important that if you design plan like we designed the drug change a single atom of the molecule affect all every property of that molecule and more.
So drug discovery can be improved by particle size and crystal crystal, different route of administration, drug delivery you have another section you will know better technique. You can use also non chemical delivery.