Medicinal chemistry Flashcards
Medicinal chemistry
It is a field focused on understanding the chemical basis of biological effects of compounds by integrating fundamental concepts from different fields such as chemistry, biochemistry, pharmacology and molecular biology
structure-property relationship
This is the relationship between a compound’s structure and its physiochemical properties:
-solubility
-membrane permeability
-lipophilicity
-total polar surface area
Structure-activity relationship
This is the relationship between a compounds structure and biological properties:
-Binding potency
-Functional Activity
-Selectivity
Physicochemical properties of compounds
solubility, membrane permeability, lipophilicity and total polar surface area
Factors that affect potency
R-group
-compounds in which the r-group is an aromatic ring will be significantly less potent than those where smaller substituents are employed
3 dimensional space
Chirality
Role of chirality
chiral means molecules are not superimpossible on each other
Chiral biological macromolecules offer an environmennt that predictably discriminates between enantiomers or optical isomers, leading to dramatic chanes in functional activity between enantiomers
Example of enantiomers
Davron and Novrad are enantiomers of each other. Davron is an analgesic that activates mew-opiod receptor while Novrad is an antitussive agent with minimal efficiency as an analgesic
Pharmacophore
It is an ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target and to trigger ( or block) its biological response.
It causes a medicinal or biological response
Auxophore
It is the remainder of the compound that may provide a structural support for the pharmacophore but plays no direct role in binding events and so does not have a medicinal function.
Example of changing pharmacophore and auxophore
Changing structure of morphine leads ti levorphanol which is four times more potent than morphine
Docking-binding score
Go through a virtual data base of compunds and assign each compund a value based on its simliarity to the lead compound. compounds with higher scores can then be identified and similar compounds can be grouped together to select compounds for physical screening.
this decreases overall cost of physical screening
Usefulness of virtual screenings
For virtual screenings to be useful, it must correlate with real-world results
Lipinski Rule of 5
-Molecular weight <500
-LogP below 5
-Fewer tham 5 hydrogen bond donors
-Fewer than 10 hydrogen bond acceptors
-Fewer than 10 rotatble bonds
LogP
Measure of lipophilicity
How well a drug will dissolve into a membrane
-High LogP means high concentration in lipid phase
-Negative LogP means compound is hydrophillic ( more soluble in aqueous environments)
-LogP = 0 means the compound is equally partioned between liquid and aqueous phase
-a desired logP is no more than 5
-A logP of1 means there is a 10:1 ratio of organic:aqueous
Lipinki assumption
Compounds are absorbed into cells via passive diffusion
Fragment based screening
Low molecular weight compounds are screened for their binding affinities to specific sites on enzymes. Fragments with high binding affinities fro different sites are then stitched together using linker units to create one compound that has a high binding affinity to many sites and therefore the overall binding afffinity of the one large compound becomes greater than the commutation of binding affinities of its individual units
