CHEM 455 Flashcards
Lead Compound
prototype having desired activity but with some undesirable characteristics that can be modified by synthesis to amplify activity or minimize undesirable properties
properties of a good lead
- interacts with desired target
- amenable to synthetic modifications
- possesses physical properties consistent with ability to reach target after administration
sources of lead compounds
natural ligands/substrates or another substance already known to interact with target of interest
screening
conducting a biological assay on large collection of compounds to identify compounds that have desired activity
random screening
no effort to bias set of screened compounds based on prior knowledge of target or known ligands
targeted screening
some prior knowledge to select compounds that are most likely to interact with target
fragment based screening
methods using xray crys. or NMR to identify simple molecules w modest affinity for a target w intent of connecting 2 or more fragments to create useful lead
ADME
absorption, distribution, metabolism, excretion
Absorption
process by which drug reaches bloodstream from site of administration
Distribution
to which “compartments” in body the drug goes
ex: some stay in bloodstream and some in tissues
Metabolism
action of specific enzymes on a drug to convert it to one or more new molecules called metabolites (can be favorable or unfavorable)
Excretion
means by which body eliminates an unchanged drug or metabolites
potency
strength of biological effect
selectivity
unintended sites of action
How to conduct SAR study
make single variable changes to molecule and track potency and other features to improve molecule and determine pharmacophore
How to determine pharmacophore
find activity cliffs to determine interactions between molecule and target
types of interactions involved in recognition/binding between ligand and enzyme receptor
- ionic interactions
- ion-dipole
- dipole-dipole
- H bonding
- charge-transfer complex
- hydrophobic
- cation-pi
- halogen bonding
- van der waal
efficacy vs affinity
efficacy - measure of max bio effect that drug can produce as a result of receptor binding
affinity - measure how strongly the drug binds to its receptor
Lipinski’s rule of 5 for POOR bioavailability
if they have 2 OR MORE of following characteristics then it's POOR: MW > 500 da log P > 5 >5 H bond donors (OH+NH) >10 H bond acceptors (N+O)
Veber’s Rules
poor bioavailability result from:
rotatable bonds > 10
high polar surface area >140A^2
total H bonds > 12 donors & acceptors
common off-targets
related family members, cytochrome P450 enzymes, specific transporters, hERG channel
Toxicophores
functional groups that have undesirable effects and functional groups that can be converted by metabolic processes to moieties that have undesirable effects
basic types of toxicophores
aromatic nitro, anilines, epoxides, aziridines, nitroso, azo, aliphatic halides, heteroatom-heteroatom bonds, polycyclic aromatic systems, imidazole
functional groups that become toxicophores after metabolism
furans & thiophenes –> epoxides
thioamides & thioureas –> electrophilic imines
anilines –> electrophilic nitroso derivatives
Clinical trials phases
Phase 0- exploratory, 10-15 healthy subjects to gather prelim human ADME data
Phase 1- evaluates safety, tolerability. 20-100 healthy volunteers unless life threatening
Phase 2- assesses effectiveness, determines side effects. few hundred diseased patients. 1-3 years
Phase 3- establishes efficacy of drug in several thousand patients. 2-6 years
Phase 4- drug is on market and assessed for real safety and tolerability. millions have taken drug
Pharmacodynamics
receptor interactions; effects of drug, potency and mechanism of action
Pharmacokinetics
depends on water solubility and lipid solubility; ADME
movement of drugs within body
types of modifications to lead compound
homologation, chain branching, bioisosterism, conformational constraint
Homologation
increasing compounds by a constant unit
Chain Branching
lowers potency if lipophilicity is important and can interfere with receptor binding
Bioisosterism
substituents or groups with chemical or physical similarities that produce similar biological properties
effects: structural, receptor interactions, pharmacokinetics, metabolism
Conformational Constraint
- if constraint retains bio activity then most likely approximates bioactive conformation
- help differentiate desired target from other proteins
- can say something about physical properties of receptor
Classic bioisosteres
peripheral layer of electrons are considered identical
Non-classic bioisosteres
do not have same # of atoms; do not fit steric/electronic rules of classic isosteres
Advantages of Computer Based Design
- proteins can be visualized in 3D
- structure can be manipulated
- binding site enlarged
- physiochemical properties of each part of receptor can be viewed
- distances between groups can be determined
- small molecules can be docked to determine their fit
Disadvantages of Computer Based Design
- XRay/NMR structure required
- Crystals obtained by crystallization of proteins happens under nonphysiological conditions
- crystal structures represent the most stable conformation but don’t predict what it will be in a living cell
- if binding ligand results in a conformational change, it is unlikely that it will occur in crystalline state
- proteins are more dynamic than rigid
- resolution is not perfect
- ligand does not have to bind in lowest energy conformation
- different geometries can have the same conformational energy but with different shapes
Importance of flexibility and conformation
receptors & proteins are flexible – sometimes lowest energy conformation of drug won’t necessarily bind to active site of receptor
intellectual property position
obtaining a patent on a drug in order to recover costs of drug discovery
