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Pharmaceutical Chemistry 2
Lecture 2 11/12/14
QSAR
The most lethal compound in this assay was chlorpromazine, with a BR (LD100) of only 0.00000631 mmol; and the least active was ethanol, with a BR of 0.087096 mmol.
It takes about 13,800 times as many millimoles of ethanol than of chlorpromazine to kill 100% of the test subjects
Partition Coefficient
Drug will go into series of partitioning steps.
(a) leaving the aqueous extracellular fluids,
(b) passing through lipid membranes, and
(c) Entering other aqueous environments before reaching the receptor
Partition Coefficient
• The partition coefficient (P) is the ratio of the molar concentration of chemical in the
non-aqueous phase versus that in the
aqueous phase.
{ chemical} oct
P = {chemical} water- Thousands of compounds
Ex. Chloroform and hexane
Partition CoefficientPhosphoglyceridessphingomyelins, galactocerebrosides,plasmalogens
unsaturated fatty acids
Application.
• Experimental determination of octanol/water partition coefficients is tedious and time consuming.
• Today, most are calculated.
- Commercial drug design software package contains modules that estimate a chemical’s P.
Other Physicochemical andDescriptor Parameters
• Hammett’s constant; • Taft’s steric parameter, Es; • Charton’s steric parameter, v; • Verloop’s multidimensional steric parameters, L,
B1, B5; • Molar refractivity, MR.• Number of hydrogen bond donors and
acceptors, pKa, polar surface area, number of rotatable bonds,
• Connectivity indices
Rules devised to maximize information
obtained
Result
• Following these guidelines, the initial test set can be reduced to 24 to 26 compounds.
Has QSAR successful?
It must be remembered that most of descriptors are only as good as the algorithms used to calculate them.
Further, it can be difficult to interpret exactly what the descriptors are measuring in chemical space. QSAR
equations must explain physical reality if predictions for future compounds are to be made.
Computer Aided DesignNEWER METHOD
• Through the use of computer graphics, structures of organic molecules can be entered into a computer and manipulated in many ways.
• Combinatorial chemistry
Pharmacophore hypotheses
HITS!!!
HIGH THROUGHPUT SCREENING
DRUG DEVELOPMENT
Drug- Receptor Bonds
• It is desirable to have the drug leave the receptor site when the concentration
decreases in the extracellularfluids.
Therefore, most useful drugs are held totheir receptors by ionic or weaker bonds.
When relatively long-lasting or irreversible effects are desired
Exemptions
• Nitrogen Mustard to be used in cancer.
known as "HN2" became the first chemotherapy drug mustine.
Type of Bond Description Examples
Covalent causes a strong
irreversibly bond to a
drug–receptor complex
Ethacrynic acid
Bonds with
Sulfhydryl
groups of ion
Transport
systems
in the renal
tubules
Selegiline
Type of Bond Description Examples
Hydrogen Bond Drugs possess groups such as carbonyl, hydroxyl, amino, and imino, with the structural capabilities of acting as acceptors or donors in the formation of hydrogen bonds.
Type of Bond Description Examples
Van der Waals forces
Attractive forces
created by the
polarizability of
molecules and
are exerted when
any two
uncharged
atoms approach
each other very
closely.
Aromatic rings
STERIC FEATURES OF DRUGS
• Steric factors determined by the stereochemistry of the receptor site surface and that of the drug molecules are, therefore, of primary importance in determining the nature and the efficiency of the drug–receptor interaction.
Example
Aromatic rings are planar, and the atoms attached directly to these rings are held in
the plane of the aromatic ring.
Geometric isomers
• Cis- and the trans-isomers hold structural features at different relative positions in space.
• These isomers also have significantly different physical and chemical properties.
Example
Trans-diethylstilbestrol is
estrogenic, whereas the
cis-isomer is only 7% as
active.
Conformational isomers
• Exist as different arrangements in space for the atoms or groups in a single classic structure.
• E- and Z-isomers.
Examples of Stereoisomers
Conformational Flexibility andMultiple Modes of Action
It has been proposed that the conformational flexibility ofmost open-chain neurohormones, such as acetylcholine,
epinephrine, serotonin, histamine, and relatedphysiologically active biomolecules, permits multiple
biological effects to be produced by each molecule, byvirtue of their ability to interact in a different and unique
conformation with different biological receptors
Acting in a trans conformation at the muscarinic receptor and not acting in a cisoid conformation
at the nicotinic receptor.
Optical Isomerism and Biological Activity
• Most commercial drugs are asymmetric, meaning that they cannot be divided intosymmetrical halves.
Although D- and L-isomers have the samephysical properties, a large number of drugsare diastereomeric, meaning that they have
two or more asymmetric centers.
Application
• Frequently, the generic name indicates a specific stereoisomer.
Examples include levodopa, dextroamphetamine, dextromethorphan, levamisole,
dexmethylphenidate, levobupivacaine, dexlansoprazole, and levothyroxine
More pharmacologic action
WHY?
The fact that most receptors are asymmetric, there are other reasons why Stereoisomers show different biological
responses.
• Active transport mechanisms-Preferential binding of one stereoisomer
over others.• Differences in physical properties
-Distribution of isomers between body fluids and tissueswhere the receptors are located will differ.
•The enzymes responsible for drug metabolism are asymmetric.
-Biological half-lives will differ among possible stereoisomers of the same molecule.
WHY?
Calculated Conformations
There will be a best shape or conformation that can be expected to fit
onto the receptor.
Quantitative methods to obtain estimations of preferred molecular shapes of receptors
Crystallography
-permits an accurate mathematical description of the molecule, providing atomic coordinates in 3D space that can be drawn by using a chemical graphics program.
• -common procedure for proteins and nucleic acids.
A computer-generated representation ofDorzolamide
The ball-and-stick minimized model isdisplayed with superimposed translucent
Van der Waals surface showing both atomicconnectivity of the molecular structure and
its 3D shape and size.
Computer-generated representation of
a thienothipyran-2-sulfonamide bound to the
active site of carbonic anhydrase.
3D QSAR
THIS molecule could have various conformations.
Is the overlap involving the tetrahedral carbon important for activity?
Should the five memberedring provide the reference points?
Which way should it be rotated? ‘
Measuring the degree ofconformational and shape similarities
• Molecular shape analysis (MSA)
• Distance geometry
• Molecular similarity matrices
• Graph Theory
Software packages
Physicochemical parameters located at specific distances from the surface of the
molecule.
Eg. Comparative molecular field analysis (CoMFA)
Molecule situated in aCoMFA grid.
CoMFA
• The hypothetical molecule is placed in a grid and its surface sampled a specified distance.
• The parameter types include Steric, Lennard-Jones potentials and other quantum chemical parameters, electrostatic and steric parameters, and partition coefficients.
• The result is thousands of independent variables.
CoMFA algorithm• is for explaining ligand–receptor interactions for a
set of molecules.
Lipinski Rule of 5.
ISOSTERISM
• Has been widely used to describe the selection of structural components- the steric, electronic, and solubility characteristics.
• Introduced by Langmuir in 1919.
Isoteres- compounds having the same number and arrangement of electrons.
Examples of isosteric pairs that possess similar steric and
electronic configurations• Carboxylate (COO) and sulfonamide
(SO2NR) ions• Ketone (CFO) and sulfone (OFSFO)• chloride (Cl) and trifluoromethyl (CF3)• Hydrogen (MH) and fluorine (MF)• Hydroxy (MOH) and amine (MNH2)• Hydroxy (MOH) and thiol (MSH)• Divalent ether (MOM), sulfide (MSM),• Amine (MNHM), and methylene (MCH2M)
groups
Examples of isosteric ringsystems
Examples of isosteric ringsystems
CoMFA in drug design
Are their commercial products that were discovered using these techniques?