Drug discovery challenges and different discovery approaches

Drug Discovery Challenges and
Different Discovery Approaches

Presentation by:- Hitesh Soni

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Drug Discovery Challenges

Withdrawn

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Drug Discovery Challenges

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Different Discovery Approches

Natural products as a source of Transient binding drugs Multitarget drugs
new drug leads and new drugs

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Drugs or Drug lead from Nature
Nature to lab to clinic
Natural compounds again become central player

History
Digitalis(1785)-William Withering-small molecule digoxin- Lead to Understanding the
biochemistry and biology of Na-K-ATPase pump

Morphine(1806)- Freidrich Serturner-Pain- Enabled to understand the Opiate receptor
subtypes and endorphine-enkephalin pathways

Aspirin (1897)- Felix Hoffmann- Salicylic acid from Willow bark-Synthesis of Aspirin from
SA- Decided the test battery of NSAIDs Like COX-2 inhibitors, Synthetic drugs, inherent
safety issues

Penicillin from mold (1928)- Alexander Fleming
Understand the Antibiotics and role of M.O.

Mid-1900s, era of Synthetic Sulfa drugs– Allergy, Resistance

20 th century- Natural Products- Endogenous chemicals- Steroids,PGs, Peptide hormones-
Played a major role in drug discovery
20 th century- Redefined enzymology and Redefined receptor pharmacology
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Biochemical assay arena- Tools for measuring the potency and Selectivity

HTS (Made natural product drug discovery impractical)

Accelerated the rate of new drug discovery

Shift from functional assays to artificial assays that measured molecular
Interaction

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Modern and advanced technologies to predict the drug interactions,

New technologies in drug discovery, like HTS, sensitive bioassays

Failure in drug development/ low success rate even though increased
Drug discovery expenditure

What’s wrong????????????

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Revisit the nature using approaches,

Lead from nature

Functional biological assay

Whole cell cytotoxicity assay

Classical Pharmacological approach and animal model

Extrapolation from Mouse-Rat-Dog-Monkey- Human???

Humanized animal models- Genetic approach

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Examples

Amphotericin B- S. nodosus- Gold standard for systemic fungal Infection- Synthesis

Rapamycin (Sirolimus)- S. hygroscopicus- Antifungal but toxic, Revisited due
to immunosuppressive properties. Rapamycin-eluting stents-approved
By FDA 2003, 2007-semisynthetic analogue-Temsirolimus-approved
by FDA for advanced renal cell carcinoma, Synthesis

Taxol (Paclitaxel)
Bark of pacific yew tree Taxus brevifolia. Taxol structure discovered in 1971.
Launched in 1992 for refractory ovarian cancer.

Paclitaxel stents approved by FDA,2004

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Drugs or Drug lead from Natural source

Path , not easy

Synthesis- very difficult due complexity but not impossible

Screening by modern technologies- possible

Evaluation in refined animal models

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Transient binding drugs
Mind set- Weak binders are undesired and no benefit.
Drug design towards highest possible binder to given target (receptor).

Fact- biological interactions are weak or transient (dissociation Constant: Kd>µM)

Transient Interactions Exerts biological effects by,
Parallel binding
Simultaneous binding between multiple sites on biological molecules
Polyvalent interactions- much strong than monovalent

Example
Dynamic binding of cells to cells, such as white blood cells rolling over the surface of endothelial
cells during inflammation. Simultaneous transient binding of selectin molecules on the surface of
one type of cell with sialyl Lewis X structures on the other cell mediates this interaction. These
interactions lead to penetration of white blood cells at the inflammation site.

Serial Binding
Repeated weak binding events
Activation of T cells during immune recognition. Signal transduction seems to be as a result of
repeated serial binding (knocking on receptor) between peptide–MHC complexes and multiple T
cell receptors.

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Weak binding (SubµM) Transient binding
Monovalent Individual weak binding With many targets
High off rates Polyvalent binding (multitarget)
Low on rates
Multivalent interactions 1+0=1
Memantine, which was recently result from simultaneous
approved for the treatment of binding of several sites 1+1=>2
Alzheimer’s disease, shows binding to on the same molecule
the NMDA receptor in the mMrange with multiple receptor
with an off-rate of approximately 0.4/s. sites.
It is clear that this approach, using
weakly binding drugs with fast off-rates, The antigen-antibody complex
could be a key factor in designing with the immunoglobulin M
effective ion-channel blockers, and that (IgM) is an illustrative example of
this principle can apply to a number of the natural existence of a
neurological and other targets. multivalent assembly that can be
composed of individual weak
Foser et al. and Bailon et al. showed that binding sites.
PEGylated interferons for treatment of
chronic hepatitis C showed decreased Anticancer
affinities (near to mM) compared to the Antibiotics to minimize drug
parent interferon, because of partly lower resistance
on rates.

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Faster kinetic


Weakly binding drugs/weak biological interactions are not studied because of difficulties in
screening or analyzing them; that is, ‘if you cannot see them, they do not exist.’
Fortunately, there are a number of emerging techniques to study and screen transient
interactions.

Specificity = desired interaction vs. nondesired interaction. Ratio may be higher for weak
binders.

Kd= 1 µM- consired as nonspecific most of the times 1 µM is sufficient to fill the half of the
receptor sites

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Transient binding drugs, Benefits
Examples of drugs that can be considered as transiently binding are alcohol (ethanol) and nonsteroidal anti-inflammatory
drugs (NSAIDs), such as aspirin, naproxen and ibuprofen. In a complex way, alcohol affects synapses of the central nervous
system (CNS) and can be considered a transient binder, because of its perceived low affinity for different receptors in the
brain where rather high concentrations are needed to produce biological effect.

Other examples of weak enzyme inhibitors are valproic acid and butyric acid, which affect histone deacetylases.

Transient binding could also be of great value to screen for weak interactions of drug candidates to targets that produce side effects,
since these effects can be subtle. Cytochrome P450 (CYP) enzymes are a group of approximately 50 enzymes that metabolize, and are
largely responsible for clearance of, many drug compounds.
It may be of interest to study the upregulation of CYP enzymes because of weak interactions of drug substances during a longer period of
time. Negative screening for weak binding to CYP enzymes has potential for selection of drug candidates with minimal CYP
interference.
Another important issue in drug discovery is receptor desensitization.It may be situations where weakly binding substances are
sufficient to cause signal transduction but not receptor desensitization.

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Multitarget Approach

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Complex conditions, such as cancer, inflammation, depression and
cardiovascular diseases, are not caused by a single molecular defect, but are
rather the result of a combination of molecular dysfunctions.

An illustrative example of a ‘promiscuous’ drug is the anti-cancer agent
Gleevec (Imatinib Mesylate) which shows promise in treatment of leukemia.
Although it was originally designed to hit a particular target, it was soon
realized that this drug was a multiple-target kinase inhibitor.

Another illustrative group of drug compounds that show a broad binding
spectrum are anti-psychotic agents where many of these bind to a plethora of
neuronal receptors

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It is clear that the ‘magic bullet’ strategy to solve complex diseases has not
been as successful as anticipated, suggesting instead that a ‘magic shotgun’
strategy may be a viable alternative for a variety of disorders

A multi-target drug will frequently be a transient binder, since it can interact
with a number of disparate targets. In other words, cross reactivity of the drug
should be substantial so that it can theoretically interact with multiple targets
for maximum efficiency.

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Finally

Perhaps most importantly,
‘old fashioned’ drug development might come back.
If you want to know the response of a complex system, ‘ask’ the
system (by testing drug candidates in complex in vivo tests)!
And, although microarray techniques might be useful to follow multi-
target drug strategies,
in vivo pharmacology (i.e. whole-animal studies) might become
important again .
Furthermore , advances in genetics leads to more-efficient in vivo
testing, better animal models are needed.
Better animal models can be achieved by ‘humanizing’ the
metabolism and signaling of test animals.
Disease target genes and their protein products might be transformed
from drug targets to core elements of better animal models in the
future.

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Drug discovery challenges and different discovery approaches

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