Forces Involved in Drug-biomolecule Target Interactions: - PowerPoint PPT Presentation


PPT – Forces Involved in Drug-biomolecule Target Interactions: PowerPoint presentation | free to download - id: 1b37fe-ZDc1Z


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation

Forces Involved in Drug-biomolecule Target Interactions:


Binding: noncovalent, reversible association (and dissociation) between molecules. Drug-target complex is more stable ... adduct. Drug-Target. Covalent adduct ... – PowerPoint PPT presentation

Number of Views:69
Avg rating:3.0/5.0
Slides: 42
Provided by: alisonm6


Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: Forces Involved in Drug-biomolecule Target Interactions:

Forces Involved in Drug-biomolecule Target
Interactions Intermolecular Forces Binding
Noncovalent binding equilibria
  • Binding noncovalent, reversible association
    (and dissociation) between molecules
  • Drug-target complex is more stable (lower in
    energy) than if the drug is not complexed to the
    target biomolecule.
  • Defined rates (kon and koff) and equilibrium
    constants (Ka and Kd).
  • Below, AM is the complex A is the free, unbound
    small molecule/drug M is the free, unbound large
  • Association equilibrium

Noncovalent binding equilibria
Dissociation equilibrium
Pharmaceutical industry
In general, stronger binding larger Ka or
smaller Kd
DG -RTlnKeq
Useful numbers 1cal 4.184J R
8.314JK-1mol-1 1.9872 calK-1mol-1)
Stabilizing Forces involved in a Drug-Receptor
  • distance-dependent.
  • possible when molecular surfaces are
  • include (covalent), electrostatic, and
    hydrophobic interactions.
  • Covalent bonding
  • 40-150 kcal/mole. Strongest.
  • Irreversible requires a chemical reaction
    between the receptor and the drug
  • rare for drug-receptor complexes.

Stabilizing Forces
Covalent bonding- example
  • Example Anticancer agent 5-fluoro-2'-deoxyuridyl
  • forms an irreversible complex with thymidilyate
  • prevents DNA from being biosynthesized
  • limits the uncontrolled cell division of cancer

Ternary Covalent adduct
Drug-Target Covalent adduct
Stabilizing Forces
Electrotstatic interactions (ion-ion ion-dipole
dipole-dipole including H-bonding charge
transfer London dispersion forces)
Magnitude can be estimated by coulombs law (E
  • Ion-ion
  • 5-10kcal/mole for opposite charges
  • Ionic compounds have a permanent (full) charge.
  • Noncovalent (reversible)
  • Effective over longer distances than other
    noncovalent interactions.

Stabilizing Forces
Electrotstatic interactions, continued
  • ion-dipole, dipole-dipole
  • 1-7 kcal/mole
  • C-Y bonds are polar when Y an electronegative
    atom such as O, N, S, halogens
  • A polar bond leads to partial positive and
    partial negative charges along the dipole.
    (Smaller stabilization than full charges)
  • Relative orientation with respect to the dipole
    will affect amount of stabilization

Stabilizing Forces
Electrotstatic interactions, continued
  • Hydrogen bond
  • 3-5 kcal/mole
  • Special kind of dipole-dipole interaction.
  • H must be covalently bonded to electronegative
    atoms N, O, or F
  • H can interact strongly with lone pairs of
  • Optimal geometry - use VSEPR to estimate location
    of lone pair

Stabilizing Forces
Electrotstatic interactions, continued
  • Cation-pi interactions
  • 1-3kcal/mole
  • electron-rich face of aromatic groups plus
    cationic/electron-poor groups

Note Pi-pi interactions
Stabilizing Forces
Electrotstatic interactions, continued
  • Induced dipole interactions
  • Polarization. A charged or polar molecule may
    induce a dipole in a nonpolar molecule. Very
    small effects.
  • Van der Waals or London Dispersion Forces.
  • .5 -1 kcal/mole
  • Instantaneous dipoles in all molecules stabilize
    one another. (induced dipole-induced dipole)
  • Larger complementary surface areas lead to larger
    London Dispersion Forces.

Stabilizing Forces
Hydrophobic interactions Two nonpolar molecules
tend to associate in water, due to an increase in
the entropy of water molecules
Additional Structural Considerations
1. pH/pKa and drug-target interactions. The
protonation state of a particular functional
group will determine its charge, and therefore
the nature of intermolecular forces
2. Stereochemistry and drug-target interactions.
Different stereoisomers can have different
activities. (Not equally complementary to the 3D
structure of the target).
Ex 1. R and S isomers of the antimalarial
chloroquine have equal potencies
Additional Structural Considerations
Ex. 2. the 1R, 2S enantiomer of norephedrine
(2-amino-3-phenyl-1-propanol) is 100 times more
potent than the 1S,2R enantiomer on the alpha
adrenoreceptor in vivo and in vitro.
Ex. 3 S-Ketamine is an anaesthetic R-ketamine
has little anaesthetic action but is a psychotic.
Additional Structural Considerations
  • 3. Conformation and drug-target interactions.
  • Both drug and target molecules may have multiple
  • Recall Morphinan from Molecular Conceptor in
    lecture 1

Drugs can have higher potency if they are
"conformationally restricted" to a bioactive
conformation. Bulky substituents or rings are
often used for this purpose
Stabilizing Forces - Summary
Keq Ka
Electrostatic interactions Enthalpic (DH)
effects. Placement of complementary groups on
drug and target. Size of charges, distance
between interacting groups, orientation.
Multiple small effects add up!
Hydrophobic interactions, conformational
restriction Entropic (DS) effects.
Free energy of Binding of drug to target
Reaction coordinate
Hydrophobicity (lipophilicity) and drug action.
Hansch and coworkers hypothesized two steps for a
drug to work Pharmacokinetics (drug getting to
the site of action) Pharmacodynamics
(interaction of drug with the site).
Pharmacokinetics phase depends on interaction
with aqueous AND membrane environments. The
ability to interact with nopolar membrane
environments can be correlated with a
water-octanol partition coefficient P.
Hydrophobicity (lipophilicity) and drug action.
  • Note optimum partition coefficient
  • if a compound is too hydrophobic, it will remain
    in the first membrane it contacts
  • if it is too hydrophilic, it will never cross
    cell membranes to get to its site of action.

Predict Possible binding interactions with targets
Predict Possible binding interactions with targets
Predict Possible binding interactions with targets
Protein kinase inhibitors bind in pocket where
ATP binds
Predict Possible binding interactions with targets
Authors note N1 H-bond with leu 83 amide NH ArOH
H-bond with Asp 145Lys 33 ArOH edge to face
with Phe80 ArOH hydrophobic pocket
Bound to CDK2
Predict Possible binding interactions with targets
Authors note N1 H-bond with met109 amide NH N3
H-bond with water that H-bonds with Thr106 (no
room in CDK2with Phe80 ArSCH3 in
pocket Quinazoline in hydrophobic pocket
Bound to p38
Predict Possible binding interactions with targets
Nonpeptide inhibitors of serine protease
cathespin G (associated with inflammation)
identified by high-throughput screening of a
diverse library of compounds.
Predict Possible binding interactions with targets
Authors note Pi stacking of 2-naphthyl with
his 57 P-OH H-bonded to His 57 P-OH H bonded to
amide NH of gly 193 oxyanion hole of serine
proteases P-OH H bonded to NH3 of lys 192 Ketone
H-bonded to lys 192
IC50 4 mM
Crystal structure showed hydrophobic residues
phe 172, tyr 215, Ile 99. Can fill this
hydrophobic pocket New inhibitor designed IC50
.053 mM for R
Drug Targets - an Overview
Lipids Carbohydrates Proteins Carrier
proteins Enzymes Receptors Nucleic Acids
Drug Targets Lipids
  • Few drugs interact with lipids
  • They often act by disrupting lipid structure of
    cell membranes.
  • Ex 1. General anaesthetics.
  • Ex 2. Amphotericin B (used to treat athletes
    foot) binds to fungal cell membranes, creating
    channels and killing fungus. Preferentially
    binds to ergosterol (in fungal membranes) over
    cholesterol (in mammalian membranes).

Drug Targets Lipids
Drug Targets Carbohydrates
  • energy sources
  • structural elements in the cell
  • involved in specific binding interactions between
    receptors and ligands.

Ex 1. Influenza virus binds to its host by a cell
surface sugar and sialic acid residue - a drug
that binds more strongly than the natural binding
site will block the viral attachment.
Ex 2. Doxorubicin (anticancer agent) linked to a
carrier with a specific carbohydrate is more
efficient at killing colon cancer cells than
doxorubicin administered alone.
Drug Targets Proteins - Carrier
Ex. Fluoxetine (prozac) works by binding to the
transporter for the neurotransmitter serotonin,
preventing its uptake into the cell.
Drug Targets Proteins - Enzymes
  • Enzymes are a major target for drugs.
  • Enzyme targets of microorganisms, viruses used to
    fight infection
  • The body's own enzymes can be targets (if there
    is an excess or deficiency of a metabolite).
  • A drug may act by binding
  • strongly but reversibly to the active site
    (competetive inhibitor),
  • reversibly to a different site (allosteric
  • irreversibly to the active site.
  • The affinity of inhibitors is determined by
    enzyme kinetics. Review any biochemistry text for
    details of this analysis.

Drug Targets Proteins - Enzymes
Ex. 1 Adenosine deaminase metabolizes adenosine
and degrades many antiviral and cancer therapy
treatments. Inhibitors will help make those drugs
more effective. A drug that resembles the
transition state of the catalyzed reaction should
bind very strongly to the enzyme active site,
improving the effectiveness of other therapies.
Drug Targets Proteins - Enzymes
Ex 2. Tetrahydrofolic acid is necessary for the
synthesis of nucleic acids. Bacteria must
synthesize it to survive (humans ingest it).
Tetrahydrofolic acid
The drug Prontosil was found to be
bacteriostatic. Prontosil is a prodrug, because
it is metabolized to form the actual active agent
p-aminobenzene sulphonamide (sulfanilamide). It
resembles the structure of the substrate
p-aminobenzoic acid (above), so it will bind to
the active site of the enzyme dihydropteroate
Drug Targets Proteins - Enzymes
Ex. 3 antihypercholesterolemic drugs.
Cholesterol major component of fatty plaque
deposits on inner wall of arteries, and 50 is
synthesized in the body. Hypercholesterolemia is
a primary risk factor for coronary heart disease.
Therapeutic goal decrease the amount of
cholesterol synthesized in the body. The
rate-determining step is the following, catalyzed
by HMG-CoA reductase
Drug Targets - Proteins - Enzymes
HMG-CoA Km 10-5M
Hydrolysis product Mimics HMG-CoA
RCH3 mevinolin lovastatin
KI 6.4x10-10M
RH compactin KI 1.4x10-9M
Drug Targets Proteins - Receptors
  • Major target for drugs
  • Receptors are used by cells for communication
  • In nerve cells, electric impulses are
    "communicated" to cells through a chemical
    message (neurotransmitter) that is received by a
    protein receptor embedded in the cell membrane.
    Binding of this neurotransmitter results in a
    biological response
  • Other chemical messages are hormones that are
    circulated through the body. They also bind to
    specific receptors, triggering a biological

Drug Targets Proteins - Receptors
  • Two main mechanisms to transmit the message from
    the outside of the cell (hormone or
    neurotransmitter messenger) to the inside of the
    cell (second messenger)
  • ion channels
  • membrane-bound enzymes.
  • Drugs may be agonists or antagonists that control
    the activity of receptors
  • Agonists act like natural messengers. To design
    a drug agonist, the starting point is the natural
  • Antagonists block the receptors from the natural
    messenger. To design a drug antagonist, the
    structure is not generally similar to the natural
    ligand. Ideally, the structure of the receptor
    would be a good starting point. If unknown, use
    information about any antagonists or even
    agonists as a starting point.
  • Ex. cimetidine (Molecular conceptor , lecture
    1) is a histamine receptor antagonist

Drug Targets Nucleic Acids
Drugs that interact with DNA are usually very
toxic because human DNA and pathogen DNA are very
similar. For cancer treatment, the only
difference between cancer cells and normal cells
is the rapid cell division. Therefore, drugs
that halt mitosis (DNA synthesis) should
preferentially halt the mitosis of cancer cells.
Ideally, a drug would be able to bind to specific
Drug Targets Nucleic Acids
Three main classes of drugs that interact with
DNA 1. DNA intercalators. Bind reversibly
between the base pairs. Disrupt DNA structure and
prevent normal functions of DNA.
Drug Targets Nucleic Acids
2. DNA alkylators. Form covalent bonds
(irreversible) with DNA. Nucleophile N, O, S
atoms in DNA that aren't sterically hindered or
involved in H-bonding. Electrophile
alkylating agent.
Anchimeric assistance
DNA Interstrand crosslink.
3. DNA strand breakers. Many complex reaction
mechanisms are being uncovered, but when these
drugs bind to DNA, the result is strand breakage.
Diversity of Targets Diversity of Rationales
This was an overview of main targets of drug
action. Each general target could take weeks of
classtime to discuss! For your
presentations/papers, you may have to research
pertinent details of the target or drug action
References Anslyn, E. V. Dougherty, D. A.
Modern Physical Organic Chemistry University
Science Books Sausalito, CA, 2004. Thomas, G.
Medicinal Chemistry An Introduction John Wiley
Sons New York, NY, 2000. Patrick, G. L. An
Introduction to Medicinal Chemistry Oxford
University Press New York, 2001. Silverman, R.
B. The Organic Chemistry of Durg Design and Drug
Action Academic Press New York, 1992. Shewchuk,
L Hasssell, A. Wisely, B. Rocque, W. Holmes,
W. Veal, J Kuyper L. F. J. Med. Chem. 2000,
43, 133-138.