SAR, Drug Discovery, and Development

chemotype

-The type of a drug passed on a prominent chemical substructure(s) contained within it

-Defines the overall chemical or structural class(es) of a therapeutic agent

-May be fully or partially responsible for pharmacological activity, or not at all

pharmacophore

-Defines the structural elements necessary for pharmacological activity (i.e., potent and productive interaction with the target)

-Usually includes a core structure with key functional groups

SAR (structure-activity relationship)

an evaluation of how changes in molecular structure correlate with changes in target activity; the relationship between the chemical structure of a drug and its physicochemical, pharmacological, and therapeutic activities

(Q)SPR (structure-property relationship)

describes how changes in molecular structure correlate with changes in a physical property such as solubility or lipophilicity

pharmacore-based (ligand based)

approach to drug design that starts with molecule with known activity of natural origin and try to modify it; create analogs and test to try to mimic activity of natural product

target-based (receptor/site-based)

approach to drug design that focuses on the structure of the target through X-ray crystallography or NMR

conformational restriction

functional group variation

isosteric modification

homologation and branching

four basic concepts of molecular modification

conformational restriction

Can involve:

-Substitution of adjacent rings with bulky groups can force one ring to rotate out of plane of the other one. This can be more favorable for during drug binding to its target or preventing a drug from being destroyed by an enzyme (ex: diclofenac)

-Replacing a single bond with a double bond can restrict rotation and force a molecule to adopt a specific stereochemistry which enhances receptor binding (ex: chlorpromazine)

functional group variation

Can involve:

-Replacing a polar group with a lipophilic group can enhance oral bioavailability and/or pharmacological activity

(Ex: Clindamycin)

-Removal of a certain functional group can inhibit metabolic enzymes crucial to the survival of viruses

(Ex: dideoxy-antiviral)

-Substitution of readily metabolizable functional group with a more stable one can extend duration of action of certain drugs

(Ex: lidocaine)

isosteric modification

molecular modification in which groups may be interchanged to generate synthetic analogs that can be defined as isosteres; may be classified as classical (follow simple rules) or non-classical (deviate from simple rules) but both are employed in developing drug candidate analogs for many diseases conditions

isosters

compounds or groups of atoms that have the same number and arrangement of outer electrons

Ex: O = CH2 = NH = 8 electrons

bioisosteres

functional groups or molecules that have similar chemical and physical properties that produce broadly similar biological properties

homologation

successively adding methylene groups (-CH2-) to a hydrocarbon chain

chain branching

insertion of methyl groups or moving functional groups in a linear hydrocarbon chain to introduce branching