Lecture 7: QSAR and Drug Development Flashcards
QSAR (Quantitative Structure-Activity Relationship)
-math models showing correlation between drug structure and actiivties
-derived by statistical regression
-information on receptor not necessary
Molecular Descriptors
-numerical parameters describing chem properties that can be directly determined from structure
-used as variables in QSAR models
Molecular descriptors examples
-drug as whole: LogP and D, molecular weight, pKa
-fragments: pi and sig values, size
Hansch Analysis
log (1/dose) = k+k’(logP)-k”(logP)^2 + other terms
Training
determines parameters (P1, P2, etc) of math models using a training set
Testing
checks validity of model using a test set
Training and Testing
-both sets contain drugs with known activity data
-can be used to predict activity of drug without known activity data
Mathematical Model example
Activity = P1 * pi value
+ P2 * sig val
+ P3 * molecular weight
+P4 * LogP
+C
Machine learning
-provide computer with extensive set of data and let it determine QSAR itself
-no math model needed
-bases of SAR is not apparent
Machine learning Mech
Structures –(molecule vectorization)–> inputs –(multiple hidden layers)—> hidden layers —–>outputs (probabiility affinity)
Drug Discovery and development
Research –> target -(lead discovery)-> lead -(lead optimization)-> drug candidate –> trials
Lead discovery
-natural products
-antimetabolites
-structure-based drug design
-high throughput screen
-in silico drug screen
Lead optimization
-structure based drug design
-QSAR
-isoteric replacement
-prodrug
Antimetabolites
-analogues of endogenous metabolites
-resemble essential metabolite and competes with metabolite in physiological reactions
-folic acid vs methotrexate
Structure-based drug design
-based on 3D structure of target protein
-rational design vs in silico screen
Zanamivir (relenza)
-flu neuraminidase inhibitor
-DANA was a transtition-state analogue
-improved binding by switching hydroxyl group with guanidino group
-approved inhaler for flu
-KI = 2 * 10 ^(-10)
DANA
-transition state analogue
-KI = 1 * 10^(-6)
Challenges of drug design
-potency
-solubility
-stability
-selectivity
-permeability
Bioisosteres
-functional groups or atoms that:
-have similar steric and electronic properties
-produce similar effects on target
Bioisosteric replacement
-improve pharmacokinetics
-improve selectivity
-reduce side effects
-simplify synthesis process
-avoid patent issues
-haloperidol?
Examples of bioisosteres
-H and -F
-aromatic rings
-S or =O bond
Prodrug
-inactive/carrier form of drug that is transformed in vivo to active drug form (usually via enzyme)
Prodrug uses
-prolong or shorten duration
-help localize drug to specific target site
-take advantage of active transport
-solve formulation problem
-decrease side effects
Heroin
-prodrug
-changes to morphine via esterases
Remdesivir (veklury)
-prodrug
-antiviral
-treat COVID
-converted to nucleotide analog that interferes with viral RNA production
You have crystallized your drug with its receptor. You see some room currently occupied by a water molecule, which makes a hydrogen bond with a positively-charged lysine group. You decide to add a group to the starred carbon to enhance the binding affinity of the drug. What group do you think will be best at that position?
Something that will make an OH
Which of the following methods is not a suitable approach for lead discovery?
Isoteric Replacement
