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New Drug Development-Screening

New Drug Development-Screening

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Published by: api-3810976 on Oct 18, 2008
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09/02/2014

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Drug screening
Drug screening
Sequence of experimentation and characterisation.
Objectives
Identifyhits
Leadidentific ation
Leadopti misation
Define the pharmacological and pharmacokinetic profile of the drug,
Methods
1. Non biological methods
2.Computational methods: Virtual screening, NMR
3. Biological methods

\ue000In vitro assays
\ue000Molecular assays
\ue000Cellular/Tissue/Organ assays
\ue000In-vivo assays
\ue000Systems or disease models

Non biological method
Virtual screening: SAR based
NMR spectroscopy
\ue000Use computational models to arrive at promising molecules for biological screening.
\ue000Promising molecules are picked up on the basis of the intensity with which the drug molecules
combine with the receptor.
\ue00010,000 molecules may be subjected to arrive at 1000 promising molecules
Biological methods
In- vitro assays
\ue000Molecular assays
\ue000Cellular/Tissue/Organ assays
In-vivo assays
\ue000Systems or disease models

\ue000Assays using biological tissues
\ue000Cell membranes,isolated whole cells,isolated tissues,isolated organs and whole animals are used.
\ue000Helps in identifying the Hits,Lead,and the Candidate drugs for further evaluation

1. Molecular assays
In-vitro assays
\ue000Detect the affinity and selectivity of the drug at the level of receptors.
\ue000May or may not detect the efficacy or the functional changes
\ue000Identification of the hit molecules(should beeffective at 50 mm conc).
E.g.

\ue000Cell membrane fractions from organs or cultured cells---source of receptors
\ue000----for affinity and selectivity
\ue000E.g.Alpha adrenoceptors to evaluate binding of alpha agonists
\ue000Enzymes e.g.Tyrosine hydroxylase from sympathetic nerve endings---enzyme

inhibition by \u2013Inhibitors
\ue000Patch clamp techniques ---for ion channels, conductance of sodium ions
local anesthetics
Advantages
\ue000Large number of molecules can be screened as high throughput screening
Limitations
\ue000Functional aspect cannot be evaluated
\ue000Other aspects like PK safety cannot be evaluated
2. Cellular assays
In vitro assays

\ue000Detect the cellular function-Affinity, selectivity and potency of the drug.
\ue000Effect on post-receptor mechanisms
\ue000Pharmacokinetics e.g.absorption across CaCo-2 cell lines
\ue000In-vitro metabolism Hep-G2 CELL lines
\ue000Hepatocytocytes and Kidney cell line-- toxicity
\ue000Drug- interaction studies
\ue000Lead identification

E.g.Islet cell culture\u2014Beta cells for release of Insulin.
\ue000Hepatocyte culture for hepatotoxic effect
Advantages
\ue000More realistic models than the molecular assays.
\ue000Post target activation/or inhibition can be studied
Limitations
Cannot assess-

\ue000Dose determination
\ue000Effect on other organ systems
\ue000Tolerability

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