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Recap:
Intermolecular forces and bindingOverview of classes of targets for drugsQuantitation of
•Drug activity (functional assay) EC50, ED50, IC50
•Drug binding (binding titration) KD, KI
Most common lab techniques (many)•Receptors - we covered radioligand binding assay•Enzymes - kinetics used (later in quarter)
Back to drug discovery:Choose a disease/conditionChoose a drug target
• Inferred from action of drug, poison, natural product, chemical signal found in humans; revealed through genomics
• Unique to a species or tissue• May require multiple targets for effective treatment
Choose a bioassayIn vivo, in vitro; high throughput screening
Two idealized approaches:Start with a known “lead compound” (isolate, purify, identify)
…Pharmacophore-based approachStart with a known target structure (isolate, purify, identify)…
Target-based approach
Hopefully, information about both lead and target are determined.
Pharmacophore-based drug design
Determine the effects of structural changes on activity of drug: structure-activity relationships (SARs)
1. Data collection: Publications; patents; biological activity; NMR and X-ray data; physiochemical properties
0. Determine identity of a “lead compound”:•Screen natural and synthetic banks of compounds for activity•Folk medicine•Natural ligand •Drug already known •Computer-aided drug design•Computerized search of structural databases
Pharmacophore: A specific 3D arrangement of chemical groups common to active molecules and essential to their biological activities
Pharmacophore-based drug design
This information will result in the identification of a pharmacophore…
2. Analysis: integrate information about drug (and target) to generate hypothesis about activity
Why make new lead compounds?•Increase activity (make binding stronger)•Decrease side effects (increase selectivity)•Improve ease and efficiency of administration to patient•Potentially find a better synthetic route
Pharmacophore-based drug design
Approach: Molecular mimicry.
If you know the pharmacophore for your target, you can create new lead compounds based on the pharmacophore!
3. Design new structures.
Pharmacophore-Based Drug Design
Simple example 1: 3D structures are known1. Data collection: biological activity of lead compound (and other compounds)
2. Analysis: biologically active molecules share the same pharmacophoric features (superimpose 3D structures&find common features)
Pharmacophore-Based Drug Design
Simple example 1: 3D structures are known
3. Design new structures. New molecular mimic will be tested.
Pharmacophore-Based Drug Design
Example 2: (A more typical example) Biologically active conformations are not known.
1. Data collection: biological activity. Two molecules below show good activity.
Data collection: Determination of biologically active conformation
Pharmacophore-Based Drug Design
Example 2 (cont):
If no 3D data are available, use computers!
•Bioactive conformations are not always the most stable conformations, but are within about 12kJ/mole or 3kcal/mole)
Data collection: Determination of biologically active conformation
Pharmacophore-Based Drug Design
•Generate low energy conformations for each active molecule:
A: Etc…
B: Etc…
2. Data analysis. Hypothesis: bioactive conformations share 3D features required for activity…Superimpose the generated conformations to define a pharmacophore
Example 2 (cont):
Data collection: Determination of biologically active conformation
Notes: •More rigid molecules have fewer conformations – easier to analyze•Flexible molecules have many conformations – often must examine conformationally restricted analogs to determine bioactive conformation. (Move from computer to lab: Chemical synthesis of analogs!) (Ex. GABA MC C2.5.2) •Superimposing molecules: don’t look at sterics only – think of physical properties of molecule.
3. Design: Use this pharmacophore to design new molecules to test
Example 2 (cont):
Pharmacophore-Based Drug Design
Superimposition of properties: Example
Dihydrofolate and methotrexate bind to the catalytic site of dihydrofolate reductase.
However, X-ray structures ofthese complexes shows that they don’t overlap as expected by sterics:
Pharmacophore-Based Drug Design
Examine electron density distribution of the molecules:
Pharmacophore-Based Drug Design
Superimposition of properties: Example, cont.
Design: use analyzed data to design new compounds - hopefully with better properties
Four Methods used to design better drugs:
1. Chemical modification
2. Database searching
3. De novo
4. Manual
These approaches generate more data, which yet again can be used to generate new hypotheses and structures, etc.
Pharmacophore-Based Drug Design
Pharmacophore-based drug design Design method 1: Chemical modification
Goal: Determine Structure- activity relationships: What functional groups are important to biological activity?
Consequences of chemical modification to drug activity in addition to altering binding interactions:
metabolism of drugpharmacokinetics
Procedure: Alter or remove groups using chemical synthesis and test the activity of the altered molecule (analog). Infer role of those groups in binding.
Pharmacophore-based drug design Design method 1: Chemical modification
Initial chemical modification: simplification
Example: ergot alkaloids like bromocriptine were starting points for simplified synthetic analogs shown below
Once a biologically active compound is found, a common first tactic is to simplify it to determine the essential parts for activity. •For complex molecules, this often leads to easier synthesis.•Will not be successful if all parts of the molecule are needed for activity
Pharmacophore-based drug design Design method 1: Chemical modification
Examples:OH isosteres: SH, NH2, CH3
O isosteres: S, NH, CH2
H isostere: FIf you change an O to CH2 - sterics same, but no dipole or lone pairIf you change an OH To SH - sterics different, but still a lone pair
O NH
amide
NH
pyrrole
Pharmacophore-based drug design Design method 1: Chemical modification
Common alterations of compounds: replacement of groups with isosteres. Isosteres: atoms or groups of atoms which have the same valency
O NH
OH
Propranolol (beta blocker)
NH
OH
S NH
OH
NH
OH
HN NH
OH
no activity
no activity
no activity active(but less than Propranolol)
example
?
Common alterations of compounds: replacement of groups with bioisosteres. Bioisosteres - different chemical groups with the same biological activity. No restriction on sterics and electronics, unlike classical isosteres.
O NH
OH
Propranolol (beta blocker)potent
O NH
OH
Pindolol very potent
NH
Pharmacophore-based drug design Design method 1: Chemical modification
Ring expansion/contractions - changes geometry
Ring variations - may add a binding interaction with heteroatom;
Pharmacophore-based drug design Design method 1: Chemical modification
Extend structure by adding a functional group to lead compound
Extend or contract linking chain length between groups
Pharmacophore-based drug design Design method 1: Chemical modification
Rigidification - limit number of possible conformationsCan help identify bioactive conformationLocks molecule in most active conformation - more effective
Add a ring
Add rigid groups
Pharmacophore-based drug design Design method 1: Chemical modification
Rigidification (continued)
Add a bulky groups (but recall it may not just affect conformaion; it may affect sterics
Alter Stereochemistry: usually different stereoisomers have different activity
Pharmacophore-based drug design Design method 1: Chemical modification
Binding role of hydroxy groups: H-bond donor or acceptor
Convert to: •methyl ether (no H-bond donor now; maybe steric problem)•an ester (no H-bond donor now; poor H-bond acceptor; maybe steric problem)
Pharmacophore-based drug design Design method 1: Chemical modification
Probing specific functional groups in a molecule
methyl ether (no H-bond donor now; still H-bond acceptor; maybe steric problem)
an ester (no H-bond donor now; poor H-bond acceptor; maybe steric problem)
Binding role of hydroxy groups (continued):
Probing specific functional groups in a molecule
Binding role of amino groups: H-bond donor (if N-H is present) or acceptor; ionic (protonation of N to form a salt; recall pKa)Convert to: •amide (no protonation; no H-bond acceptor now; steric problem?)•Tertiary amine (no H-bond donor now; still H-bond acceptor; sterics?)
Binding role of aromatic rings, alkenes: hydrophobic; cation-piConvert to: •Saturated compound (not effective overlap; no pi system; more flexible)
Probing specific functional groups in a molecule
Binding role of ketones: H-bond acceptor; dipole-dipoleConvert to: •Alcohol (geometry change can weaken H-bond or dipole-dipole)
Probing specific functional groups in a molecule
Binding role of alkyl substituents: hydrophobics/stericsConvert to: •Longer (homologation) or differently-branched groups
Alkyl groups most easily modified are
DRUG OR DRUGO
OR
DRUGO
RO
DRUGO
R
HN DRUG
O
NR2
DRUG NCH3
R
Probing specific functional groups in a molecule
Binding role of alkyl substituents (continued)
Notes: •Recall impact of lipophilicity on drug transport through body•Changing alkyl groups may also affect the preferred conformation of the molecule!
Probing specific functional groups in a molecule
Example: Nifedipine analogs
Chemical synthesis of analogs help validate or refute hypotheses regarding mechanism of action/mode of binding - part of design
O2N
N CH3H3C
CO2CH3H3CO2C
H
NifedipeneTreats hypertension
O2N
N CH3H3C
CO2CH3H3CO2C
H
CH3
Inactivesteric "bump"
O2N
N CH3H3C
CO2CH3H3CO2C
H
InactiveDifferent conformation
CH3
Probing specific functional groups in a molecule
Binding role of alkyl substituents (continued)
Binding role of aryl substituents: various/ stericsConvert to: •Same substituents at different locations•Different substituents: Recall substituent effects in organic chem!•Substituents may affect each others’ properties (pKa)
ONR
OMeSO2NH
6
8
7
Anti-arhythmic benzopyranBest when substituent was at position 7
Probing specific functional groups in a molecule
Example: beta-adrenergic drugs, chemically related to adrenaline and noradrenaline.
Probing specific functional groups in a molecule
Binding role of aryl substituents: (continued)
Binding role of amides: H-bond acceptor; dipole-dipoleConvert to: •Hydrolysis products (but will lose a piece); reduce (no more H-bond acceptor
Probing specific functional groups in a molecule
As computer analysis becomes more widespread, a pharmacophore will be less “visual” and more numerical, with numerical scoring of properties
Pharmacophore-based drug design Design method 1: Chemical modification
Activity data for modified drugs leads to a better pharmacophore
•Use databases of known compounds – no new synthesis!•Be careful of multiple conformations•Content of database is crucial
Example. Protein kinase C enzymes are targets for chemotherapeutic intervention against cancer. The pharmacophore was deduced from active phorbol esters like PDBU
Pharmacophore-based drug design Design method 2: Database searching
a. 3D Search for a 3D pharmacophore
The 3D database search led to the discovery of a new potent protein kinase C inhibitor that is chemically very different from the original reference phorbol esters. Alignment of the two:
Pharmacophore-based drug design Design method 2: Database searching
Start over with this “hit” as a new lead; chemical modification, etc…
b. 3D Shape searching on Databases - also finds chemically different compounds, but is successful only if the pharmacophore is also incorporated
Pharmacophore-based drug design Design method 2: Database searching
Assemble disconnected functional groups (pharmacophoric groups) with spacers with or without computer algorithms; using models or computer modeling software
Example. 5-alpha reductase inhibitors inhibit the metabolism of testosterone, and are used to treat prostate hyperplasia. The steroid structure has side effects. Replacement with other structures should help...
Pharmacophore-based drug design Design methods 3&4: De novo design and Manual design
Computer algorithm was used to obtain the following compounds:
Overlay of one “hit”:
Other “hits”
Pharmacophore-based drug design Design methods 3&4: De novo design and Manual design
Patrick, G. L. An Introduction to Medicinal Chemistry; Oxford University Press: New York, NY, 2001
Silverman, R. B. The Organic Chemistry of Drug Design and Drug Action ; Academic Press: San Diego, CA, 1992.
Thomas, G. Medicinal Chemistry An Introduction; John Wiley and Sons, Ltd.: New York, NY, 2000.
Williams, D. A.; Lemke, T. L. Foye’s Principles of Medicinal Chemistry; Lippincott Williams and Wilkins, New York, NY, 2002.
Molecular Conceptor, Synergix: C1 “Rational Drug Design” C2 “Structure Activity Relationships”E1-3 “Pharmacophore-Based Drug Design”
References