Samenvatting
Samenvatting Medicinal Chemistry And Biophysics
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Summary medicinal chemistry and biophysicsLecture 1: Biophysics: introduction and thermodynamics Groves 27-09-2021
Drugs
Drugs that given to the body have different functions, based on their 3D
structure. It determines membrane passage, binding to targets, metabolism and
pharmacokinetics. Paracetamol and aspirin have very similar effects, but their mechanisms are really
different due to different 3D structures. Drugs need to pass membranes passively (lipophilic, apolar) but
they also need to be able to be transported in the bloodstream (hydrophilic, polar). Therefore, most drugs
are amphiphilic (both polar and apolar). LogP is a measure of lipophilicity (see formula).
Lipinski’s rule of 5
Lipinski compared good drugs to each other and observed some similarities. Drugs are often successful if
they possess the following characteristics (all have to do with the number 5):
• Molecular mass of less than 500 Da
• LogP less than 5 (which is fairly hydrophobic; 10000 times more soluble in octanol than in water)
• Less than 10 (= 2 x 5) hydrogen bond acceptors (-O-, -N-)
• Less than 5 hydrogen bond donors (NH, OH)
Lipinski’s rule of 5 incorporates the fact that good absorption requires good solubility in both water and
membranes. Membranes consist of phospholipids, that have a polar head group and a hydrophobic tail.
The hydrogen bonds in drugs are often there to ensure correct binding to targets.
Drugs binding to targets
In 1913, Paul Ehrlich stated that there must be binding to get an effect. There was a
block model that described this. Later, the ‘blocks’, that represent both the drug and the
target, seemed to have forms, that fitted into each other. This is called the Lock
and Key model. Eventually, it was discovered that the binding process between a
drug and its target is dynamic, making the fit more precise. This is called the
induced fit model. Proteins contain rather mobile elements.
Thermodynamics and kinetics
Binding can be described by thermodynamics, creating an equilibrium (Keq) and by
kinetics, describing the speed of the process (k). If the drug is good, it is more
present in the bound state, shifting the equilibrium towards the bound state.
Interactions between drugs and targets can be covalent (no equilibrium, only kinetic
rate) or non-covalent (equilibrium and two kinetic rates).
Gibbs energy
For a reaction (in this case binding of the drug to the target) to occur, the change of
Gibbs energy (ΔG) should be negative. If ΔG is positive, extra energy should be
added in order for the reaction to occur. ΔG is determined by change in enthalpy
(ΔH, heat) and change in entropy (ΔS). If ΔH > 0: endothermic reaction. If ΔH < 0:
exothermic reaction. Ion-ion bonds and hydrogen contribute to enthalpy,
hydrophobics contribute to entropy. Upon binding, the ligand cannot move freely
anymore, this also contributes to entropy. Entropy and enthalpy modifications can
compensate each other and can sometimes be added to
create the ideal lead.
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,Lecture 2: Medicinal chemistry: Overview, patents, drug-like properties, barriers,
BBB Domling 28-09-2021
Medicinal chemistry is involved with designing, synthesizing, and developing pharmaceutical drugs. It
involves identification, synthesis, and development of new chemical entities suitable for therapeutic use. It
also includes the study of existing drugs, their biological properties, and their quantitative structure-
activity relationships (QSAR).
Drug discovery
During the process, first there is discovery, using biological target identification, activity, selectivity,
chemical synthesis and property profiling. Later there is development: batch synthesis, analytical release,
formulation and stability, human efficacy, safety, and trials in different phases. If approved, it can be
manufactured and used in patient therapy, while monitoring for side effects and enhancing the formula
where needed. A good drug needs to possess both pharmacological properties (properties involving the
selective binding of the drug to the target to achieve the biological effect) and drug-like properties
(properties that ensure that the drug is exerting its biological effects in the complex human body with
acceptable toxicity, so bioavailability permeability, stability, solubility). Only when a drug has plenty of
both property groups, there is a high-quality drug. Nowadays, often
the hypothesis driven drug design is used, in the form of the design-
make-test-analyze cycle (DMTA cycle). New compounds are designed,
synthesized, and tested, after which data is obtained that is used in a
new cycle for drug design. This way, compounds are put into clinical
trials quickly.
Evolution of drug discovery
Back in the days, drugs were tested directly in living systems, whereas today, in vitro high-throughput
screening is used. Initial hits have changed from natural products and ligands to large libraries of diverse
structures. Compound design has been improved with the help of x-ray crystallography, NMR and
computational modeling. The process has been miniaturized and automated, leading to acceleration.
Drug-like properties
Drug like properties include structural properties (H-bonds, polar surface, lipophilicity, shape, MW,
reactivity, pKa), physicochemical properties (solubility, permeability, chemical stability), biochemical
properties (metabolism, protein and tissue binding, transport), and pharmacokinetics and toxicity
(clearance, half-life, bioavailability, drug-drug interaction, LD50). Most of these properties are controlled
by modification of the structure of the drug.
Drug lifetime
Pre-clinical R&D takes several years, including the discovery and
optimization (about 3 years). When IND (investigational new drug)
arrives, there are clinical R&D trials in several stages on volunteers
(about 9 yeas). If the drug works and isn’t toxic, NDA (new drug
application) arrives, which is the marketing phase (post clinical R&D,
takes about 7-13 years). In this phase, the company that designed the drug has a patent and is able to
make money. Finally, the generic phase starts, where every company is allowed to produce the drugs, and
the prices declines drastically.
Drug failure
Back in the days, drugs mainly failed due to pharmacokinetics and lack of efficacy. Over the years, the
pharmacokinetics have been optimized in the preclinical R&D phase. Also, a big part of the failure was due
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,to lack of efficacy, which hasn’t been improved. This means that the drug is not showing the wanted
effects: probably the drug focuses on the wrong target (poorly understood underlying biology). In the
preclinical phase, drugs that are toxic are filtered out. However, most of the drugs that fail do this between
phase II and III of the development phase due to efficacy. This is a shame because at this point already a lot
of money has been invested. Drug discovery and development has become more expensive over the past
40-50 years. Preclinical development is now cheaper than clinical development.
Causes of poor outcomes in drug discovery
Poor outcomes in drug discovery can be cause by poor properties, like low bioactivity in in vitro bioassays
(solubility of the compound in the essay medium, or chemical instability in the test matrix), poor
permeability of the compounds through the cell membrane, poor penetration of the blood brain barrier or
poor efficacy in vivo (low concentrations because of poor PK, low bioavailability, or instability in the blood).
So poor properties regarding solubility, chemical and biological stability, permeability, and bioavailability
might lead to poor results in discovery. Properties can be improved by altering the structure.
Field of focus: both SAR and SPR
When only focusing on activity, very effective ligands for target
proteins can be formed. However, the properties may be inadequate to
become successful drugs (stability, solubility, PK, etc). Therefore, during
drug discovery, the focus lies on both structure activity relationships
(SAR, the change of the activity upon change in chemical structure) and
structure property relationships (SPR, the change of the drug-like
properties upon change in chemical structure). Combining both leads
to better, faster and lower risk discoveries, and on top of that more
patient acceptance and compliance. Use of SAR mainly leads to strong
target binding, whereas use of SPR mainly leads to high performance at
in vivo barriers.
Drug dosing
The goal is an oral drug (tablet) that only has one administration a day. When there are in vivo barrier
issues, more frequent dosing, higher doses, different administration, or different vehicle of formulation
should be used. Other ways than oral administration are injection (intravenous, intramuscularly,
intrathecally subcutaneously), sublingually (under tongue), rectally, vaginally, ocular, nasally, topical,
transdermal or inhalation
Drug classification
There can be a distinction made between diagnostics and therapeutics. In therapeutics, there are chemical
drugs (synthetic, natural products, new modalities) or biological drugs (mAbs, proteins). Drugs can also be
divided on indication area (anticancer drugs, anti-inflammatory drugs, anti-infection drugs). Finally, drugs
can be classified according to their target (kinases, enzymes, GPCR).
Chemical drugs
An example of a very famous synthetic blockbuster drug is atorvastatin, which is a drug that lowers
cholesterol. It is discovered by Pfizer and its synthesis takes 7-8 steps. Synthetic drugs are often
heterocyclic. An example of a natural product is galanthamine, isolated from Caucasian snowdrop (a plant)
and used in Alzheimer’s. The size is like that of synthetic drugs but it contains many sterol centers.
Therapeutic areas
In cancer, Taxol is used, which is a natural product from the Pacific yew tree. It inhibits cell division by
binding and stabilizing microtubules.
During inflammation: aspirin and ibuprofen inhibit COX2, which normally leads to prostaglandin synthesis.
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, In the case of an infection, Imipenem is used (a beta-lactam antibiotic), which kills g+ and g- bacteria by
inhibiting cell wall synthesis.
Biological drugs
Monoclonal antibodies (mAbs) are used for example in breast cancer. The mAb used is called Herceptin,
which targets Her2, which is a tyrosine kinase that is overexpressed.
In diabetes type I, a protein called insulin is used. It is a peptide hormone produced by the beta cells of the
pancreas.
Target classes
Kinases add a phosphate to a compound to activate or inhibit it and serve a function in signal transduction
cascades. Gleevec (Novartis) is a kinase inhibitor used for the treatment of chronic myelogenous leukemia
(CML).
GPCR are membrane bound receptors. Morphine acts on this to kill the pain.
Antibody drug conjugates (ADCs)
Antibody drug conjugates are antibodies linked by a linker to a potent toxin. The mAb part
brings specificity to a receptor on target cells. After binding, the complex is internalized via
endocytosis. It is cleaved by for example protease mediated cleavage or redox cleavage,
and the toxin is released to serve its effect. Often the cancer cell is killed by this process.
Intellectual property patents
A patent is a set of exclusive rights granted by a state to an inventor or his assignee for a limited period of
time in exchange for a public disclosure of an intervention. It contains claims that define the invention that
must be new, inventive and useful. A patent has to be filed in all important markets. Initially, it is about
€60, after 20 years several €100k. There can be a composition of matter patent (patent on a compound
with activities and presumed application) or a production of matter patent (a patent on a way to produce a
certain compound). First a national patent application has to be filled in, which has a grace period of 12
months. Then, internationalization has to be done (PCT). The patent has to be defended in court, and the
IP must be protected by patent surveys and buying of complementary IP.
A patent is there to guarantee a freedom to operate to the owner for 20 years. Without patents, no
companies would invest billions of dollars to generate a drug. When filing a patent, a patent search must
be done to see if the invention is novel (espacenet, google patents). Also, the structure can be seen online
(SCI finder, CAS and Beilstein). Chemical structures are only partially incorporated in databases.
Substructure searches can also be done, with the best outcome if a compound has never been described
before. If you describe a new application of an existing compound, a use-patent can be requested.
A patent contains an introduction (background, problem to be solved), description of invention (scaffolds,
synthesis, application, formulation), examples (the more the better, the detailed the better) and claims
(onion model).
Lifetime extensions can be made using generic drugs with new formulations, allotropic modifications, salts,
new indications, prodrugs, chiral switch, dose switch, active metabolites or deuterated drugs (switching
hydrogen with isotope). Generic drugs are drugs that are produced without patent protection. General
patent strategy is: after invention; matter of composition patent (20 years). After synthesis optimization;
production patent. The generic companies start working on the new drugs before the patent is invalid, to
bring it on the market directly after the patent ends. A generic drug must be the same as the original:
similar side product profile (<0.5% impurities) and bioequivalent. It is much cheaper to bring a generic drug
on the market, since you rely on the research of the original company. Example: Sorafenib, a blockbuster
drug from Bayer, costs $4500 a month, whereas Natco Pharma has the same compound for only $140 a
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