Notesale: Turn your study into money

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medicinal chemistry includes isolation of compounds of nature
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Once you have a small
molecule or a drug, you also need to look at the structure activity relationship which is basically nothing
but trying to figure out which structure leads to the best activity
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modern medicinal chemistry relies a lot on how to
rationally design a drug
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we will look at the entire process right from the
idea to where it gets into how it gets
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This is an example of how one could use traditional medicine to actually discover a drug
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There is another example of serendipitous discovery
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This led to the discovery
that he hypothesizes that the mold must secrete a substance which repressed the growth of bacteria, which
then repressed growth
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A lot of
medicinal chemistry relied on chance to discover new drugs
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So there are other ways
in which one could do this one is to look at metabolism
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Modern drug discovery does not rely exclusively on these processes, but they would want to do what is
known as a rational drug design
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Starting points for us to make compounds
that can go and interact with a protein
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The other major target other than proteins are nucleic acids such as DNA and RNA
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So therefore, if one could
develop a molecule which can interact with DNA, then it is possible that we may be able to discover a drug
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Most assays or most modern
discovery methods depend on cellular assays
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animal models are used pretty much towards the end of the preclinical
evaluation
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One of the approaches to finding a lead is to use the
natural ligand or substrate for the target
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So therefore, using dopamine as the starting point one could develop

a new lead compound or even a drug
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In the past 20 or 30 years there have been a large number of technological advances which allow for
thousands of compounds to be screened in parallel
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These compounds whose structure
we already know because we have assembled the portfolio of compounds or these compounds are taken for
further structural modifications
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Once we have this information that becomes the
foundation for us to screen for more molecules
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So there are certain interactions which are important in the binding site, and those interactions
are exploited to design compounds to hit them to hit the target
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Intermolecular Binding Forces
Drug discovery is basically trying to find the lead
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The vast majority of drugs that are used today are targeted at
proteins
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The sequence in which these
amino acids are arranged is called the primary structure
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There is a coiling of the protein such that the
peptide bonds make up the backbone
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So here Interestingly, what happens is that the R group, which is the
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So this results in minimizing the steric interactions and stabilizing the structure
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These functional groups can interact and this interaction can actually be attractive or repulsive
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Of course, There are large number of
scientists who have
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An ionic bond is nothing but an interaction
between a positively charged species and a negatively charged species
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When you have a
carboxylic acid, it usually exists as carboxylate and if you have an amine, it exists as ammonium
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The next important interaction which we
refer to earlier was hydrogen bonds
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Acids such as lysine and arginine
and histidine
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These
interactions are weak in nature and typically weaker than a hydrogen bond
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An understanding of these interactions is crucial to designing effective drugs that will target these binding
sites
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These quaternary structures are nothing but when two proteins interact with one
another and they can exist as dimers or tetramers and so on
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These sugars are present on the
surface of cells and they are really important when it comes to cell recognition
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This help with determining how
the drug interacts with a cell
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Protein Structure and Function
The first class of protein that we shall look at are structural proteins
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The next class of proteins that are important are transport proteins
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And they are also very important in transporting
neurotransmitters back into the neuron
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By the 1950s and 60s, there were hundreds of enzymes that had been
discovered and many were purified and also crystallized… In 1960, Stein and Moore shared a Nobel Prize
in 1972 for discovering the methodology of protein sequencing
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Reaction is about 10 power 8
times faster than the uncatalyzed reaction
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The general understanding of how enzymes function is that they lower the
barrier or reduce the energy required for the starting material to go to the product
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The first one is to bind the substrate
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The third part, which is basically
disassociation is also important because if the product binds very strongly to the enzyme, then the turnover
is not very good and the catalyst is not going to function very well
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This is a very interesting and important hypothesis
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The next set of hypothesis that came
up was the induced fit hypothesis
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Once it is bound the substrate
has to undergo a reaction
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The reaction is easier
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It is also possible that maximizing
these bonding interactions may force the substrate into the ideal conformation where the reaction can occur
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Introduction to Receptors
we will focus on understanding mainly the structure and how structures of the receptors and how they
function
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Pain, depression, in some cases
heart failure, asthma and some neurodegenerative disorder, all in some way shape or form connected to the
dysfunction in receptors
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Langley
showed that there is a target which responds to chemical messengers
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Even when the neurons supplying this cells
were dead
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Each target cell has a large number
of neurons, communicating with it and off course
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Each of
the cell
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Number of receptors which can communicate with different types of
neurotransmitter
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receptors are typically
identified by the specific neurotransmitter or hormone that interacts with them
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All receptors are
activated by the same chemical messenger in exactly the same way throughout the body
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a receptor is a protein which
is usually located or embedded within the cell membrane
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The area where the receptor or where the messenger binds is
known as a binding site
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The
important difference between enzymes and receptors is that the chemical messenger that transmits the signal
in the case of receptor remains unchanged
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, but if the receptor changes its conformation a bit
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In reality, both the messenger and the
binding site would probably undergo conformational changes to maximize the bonding forces between
them
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Receptor Types and Functions
there are three major families of receptors
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all three of
these are extracellular receptors and we shall also look at certain types of intracellular receptors
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The other type
of ion channels are not controlled by ligands, but instead are sensitive to differences in potential that that
exist across the cell membrane, which is also known as the membrane potential
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About 30 % of all drugs
on the market act by binding to these receptors
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G proteins interact with membrane bound enzymes and continue the signal
transduction process
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We shall look into detail about both ion
channel receptors as
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This kinase linked receptors are
activated by large number of polypeptide hormones, growth factors and cytokines
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Over expression can
result in malignant growth disorders, so therefore, these constitute important target for drug discovery
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Once
the messenger has to cross the cell membrane, it can bind to the receptor and once the receptor ligand
complex is formed
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The dimer then binds to a protein known as the coactivator protein,
and this together can go and bind to particular region of the cells
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Depending on the complex involved
the binding of the complex to DNA either triggers or inhibit the start of transcription
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Pharmacokinetics
a majority of drugs act one of the
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So drug does not act on the cell on the
whole, but instead it acts pretty much a specific target
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It can also be a receptor
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Helps with signal transmission
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Information
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RNA also carries information about how proteins are
synthesized and RNAs themselves can be catalysts
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So after we understand this we also
want to put this in perspective of the human body
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An Important characteristic of a drug is that it must survive the stomach
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Then it enters the upper intestine where it encounters further
digestive enzymes, and this helps to break down the food further
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so the drug actually passes between the cell rather than passing through them
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The
major role of the enzymes is to make the drug or the foreign molecule into easily excretable species
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The drug then has to be carried by the blood supply around the body
to reach its eventual target
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Solubility
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, so the drug must be stable to chemical and enzymes
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if the drug is too hydrophobic, it will be poorly
soluble and what happens is it dissolving in these fat globules
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Amines are often involved in drug s binding interactions
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When are in the neutral form they can actually be fat soluble and
when they are protonate they can be water-soluble
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The hydrophilic or hydrophobic character of the drug is a crucial factor in affecting absorption
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So there are many examples of compounds
which have high molecular weight, but can be easily absorbed through the gut
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So Lipinski came up with his rule of five
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Drug itself
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it is from these that oxygen, nutrients and drugs can escape
into the neighboring area
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each
capillary probes every part of the body, such that no cell is more than 20 to 30 microns away from a
capillary
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Some of these
include local anesthetics, enzyme inhibitors because enzymes are present within a cell
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Those again have to get across the cell membrane and then act on
its target
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But drugs that are excessively
hydrophobic are absorbed into fatty tissues and they are removed from blood supply
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And, so fat solubility can lead to many various problems
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The blood
capillaries that feed the brain are lined with very tight filling cells
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The ability to cross the blood brain barrier has an important bearing on analgesic activity of opiods
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The mother ‘s blood provides
the fetus with essential nutrients
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, but these chemicals must pass through what is known as the placental barrier
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The
increased concentration of the drug is actually results, right
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May actually
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Is unexpected

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