Medchem Exam 3

What type of molecule are the majority of drugs?

Small molecule

Fates of drugs in the body

1. Protein binding

2. Tissue depots

3. Elimination (unchanged)

4. Chemical decomposition

5. Drug receptor complex —> Pharmacoloigcal response

6. Metabolic alteration via Drug metabolizing enzymes

Major sources of drugs old and new

1. Natural extracts

2. Natural products —> pure molecules isolated from nature (Antibiotics and cancer agents)

3. Synthetic drugs (we make them)

4. New drugs and existing drugs (Slight modification of existing drug —> New function)

5. Screening synthetic Chemical and Natural product libraries —> Put a collection together and screen for drug

6. Rational Drug Design —> We know enough info that we can make a molecule that works

7. The role of serendipidy—> Drugs discovered by accident

Natual extracts and products as source of drugs

Sole source of new drugs for thousands of years

Natural drugs are usually more complicated and contain more rings than synthetic drugs

Approved drugs are more natural product like → reflects the success of natural product based drugs

Ex: Epibatidine

• Took sample of skin secretion from posion tree frog and tested it for biological activity

• 200 times more potent than morphine and was not an opiate and was a nicotinic antagonist

• Had SE in humans but was solved by synthesizing many variants

• Currently an important research tool

Syntheic drugs as source

The carbon source of synthetic drugs is petroleum

2% of petroleum is used for petrochemical precursors for pharmaceuticals, plastics, pesticides, perfumes, dyestuffs, food additives, etc.

Synthetic libraries are often too conservative in their structural properties

EX:

Aspirin —> One of the first semi-synthetic drugs prepared by acetylation of salicylic acid

Chloral hydrate → Synthesized by chlorination of ethanol and used as a sedative

Chloroform and ether → synthesized from ethanol and used anesthetics

*Considering nature has been making drugs for billions of years there have been many drugs that have came and gone, and these molecules often fail in trials because of the absence of a

thorough phenotypic selection process

Making new drugs from existing drugs

Small modifications in existing drugs leads to discovery of new functions of a drug

Ex:

Promethazine which was made from antimalarial phenothiazine dyes has antihistamine effects

Chlorpromazine was further discovered serendipitiously by altering promethazine

Further modification of chlorpromazine via bioisosteric replacement lead to discovery of imipramine

Screening chemical libraries and natural product libraries

Researches can screen chemical libraries (such as chemical dyes) or plant extracts for drug applicability and if a match is found it can be formulated into a drug

Ex:

Paclitaxel (Taxol) → Anticancer drug

Plant extracts from around the world were tested for anticancer activity

High Throughput Screening

Test each molecules or mixture of molecules against a validated drug target or organism

What is required for a good high throughput screen (HTS)?

• Robust assay that assess a validated drug target

• Assay must be statistically sound

• Assay should be rapid and inexpensive to assess many molecules

• The library of molecules should be novel and contain a variety of potentially active substructures (potential pharmacophores)

• The molecules should be at least slightly water soluble and not prone to aggregation

*Recently, molecular docking algorithms have progressed to allow high throughput in silico screening of large molecular databases to find molecules that bind to a given protein drug target

Rational drug design

uses knowledge of drug target structure or enzyme mechanism (or both) to discover molecules that bind and modulate the activity of the target

Ex: HIV protease inhibitors

• Serendipity played a role – sequencing of HIV showed it contained a protease related to pepsin and thiapepsin, already well-studied aspartic proteases

• It was immediately hypothesized that pepsin inhibitors already developed could be an excellent starting point for an anti-HIV protease based drug

Ex: Carbidopa adjunct

Carbidopa is an inhibitor of Amino Acid Decarboxylase, the enzyme that converts L-DOPA to dopamine. Crucially, carbidopa, unlike L-DOPA, does not cross the Blood Brain Barrier

Serependipity in Drug Discovery

Finding a new drug by accident

Ex: Cisplatin

Saw a similarity between mitotic spindle and magnetic force lines

Subjected E. Coli to electric current in aqueous NH4Cl and “inert” PT electrodes

The drug discovery and development process

Takes a lot of time (>10 years) and money ($2 billion) to approve a drug

Lead Optimization

The initially discovered or designed lead molecules for a given drug target are almost always not the final drug structure

This is because the structure needs to be optimized for a number of important attributes that make a small molecule a good drug

Some important characteristics of a good drug:

• Good oral bioavailability – water soluble but also small and lipophilic

• Chemically stable – acid stable for oral activity, hydrolytically stable

• Chemically unreactive – low or no reactivity with nucleic acids or proteins to avoid mutagenicity or immune response

• Metabolically stable – resistant to enzymatic breakdown in the body

• Pharmacologically specific – no off-target binding

• Potent but not too potent – potency is usually necessary for specificity

• Good toxicity profile – wide therapeutic index to avoid toxic side effects but the activity usually needs to be intermittent, especially in the CNS

• Inexpensive to manufacture – fairly simple structure for chemical synthesis or able to be prepared by fermentation (not Taxol, for example...)

Why do drugs fail in devlopment?

Toxicity is the overwhelming issue in preclinical drug development

For clinical studies, it is a combination of safety, efficacy and commercial

Issues with efficacy is that the wrong drug target is selected

But we’ve made significant progress improving PK and bioavailability

Noncovalent Interactions

The unequal distribution of electron density in molecules results in electrostatic interactions between and within molecules

Electron density is not uniformly distributed in most molecules

• The carbonyl nitrogen bond has significant double bond character

• The amide bond has a large partial negative charge but so does the nitrogen

The crystal structure of this drug shows that the N group has a short bond character which is evidence for the third resonance structure

• Theoretical calculations can now provide a better idea of how a molecule can interact with other molecules as well as its reactivity

Dipole bond moments and electronegativity

Bond moments are proportional to the difference in EN of two atoms

• The more EN an atom is the larger the bond moment

• A larger number indicates more polar covalent bonds that a more e- withdrawing

Distance dependence of Noncovalent interactions

Ionic Interactions (Charge-Charge)

• Ions are solvated by water which competes with this interaction

• However, in a protein binding pocket water may be excluded, which enhances the energy of the interaction

• Energy is proportional to 1/Dr where D = dielectric constant and r = distance

Often PH dependent

Dipole-induced dipole interactions

Dipoles can be permanent or temporarily induced by a nearby charge or occur by random fluctuation of electron density in a nonpolar group

• Charged ions can also interact with permanent dipoles and can induce dipoles in other molecules or within the same molecule

London Dispersion / Van der Waals interactions

There is an optimal distance between any two atoms that is energetically favorable

The attractive dispersion force is typically induced dipole interactions and are proportional to 1/r6 , while the repulsive force is prop. to 1/r12

• This means too far away no benefit and too close together huge energetic penalty

The Dispersion induced dipole – induced dipole interaction is related to the “polarizability of the atoms involved. This is proportional to the distance of the valence electrons to the nucleus. Sulfur and bromine, iodine are examples

The large number (n) of van der Waals interactions (n x 0.5 kcal/mol) can add up to a significant amount of binding energy, but only if the atoms are close → This explains the importance of “fit” between a drug and it’s protein target binding site

Hydrogen bonding

An electrostatic interaction between heteroatoms (N,O) and hydrogen atoms bound to heteroatoms → Can be considered a special case of a dipole-dipole interaction

• Strongest when linear (nonlinearity does not greatly decrease energy of interaction)

• All atoms remain neutral

Ex: Water can solvate polar groups

Ex: Proteins use hydrogen bonding to interact with polar groups in small molecules and use intramolecular H-bonding to fold into secondary and tertiary structures

Clinical effect of a hydrogen bond

The antibiotic Vancomycin kills gram positive bacteria by clamping down on the D-Ala-D-Ala terminus of its peptidoglycan.

• A hydrogen bond from the Vancomycin to the amide of the D-Ala-D-Ala is key to binding

Basically, strains were isolated in which the peptidoglycan had an ester in the place of the amide which decreased the binding affinity by 1000 fold rendering the antibiotic useless

Cation - Pi interaction

A special Ion - Dipole Interaction

Cation - PI interaction: A non-covalent interaction between the face of an electron-rich system (i.e., benzene) and a nearby hard metal cation (i.e., Li+, Na+, K+), or a softer, more diffuse ammonium cation (i.e., NR4+).

An Electrostatic-Like Interaction: Positive charged species being attracted by the negative PI-electron cloud (or PI-cloud)

• The more negative the ring surface is, the stronger the cation-π interaction

Cation PI AcHE Example

In AcHE, Trp-84 forms a cation-pi interaction with the N-(Ch3)3 group

This binding allows for AcHE to degrade AcH which is important for regulation

Entropy

A measure of uncertainty or probability —> specifically related to the number of microstates available to a system for a given macrostate

If a system has a greater number of possible microstates or greater uncertainty—> greater entropy

Second law of Thermodynamics

The entropy in the universe always increases for spontaneous processes.

Always released in the form of heat

Molecular interactions and entropy

Entropy is increased when the system has more possible configurations or microstates

Examples:

• Molecules with translational freedom have greater entropy than those that are ordered or in bound arrangements where movement is restricted (Molecules in crystal vs solution)

• Molecules with greater freedom of rotation have greater entropy than those that are rigidified in rings

• For a spontaneous process, change in G < 0

  • According to the second law of thermodynamics the total entropy is always increasing

Hydrophobic effect

Placing nonpolar molecules in water (polar solvent) is energetically unfavorable

• Due to dipole-induced dipole noncovalent interactions

  • The restriction of motion reduces the entropy of the system → Entropic cost

Desolvation and the hydrophobic effect

Oil molecules interact with each other to create one giant oil droplet which has less SA to cover with ordered water molecules —> Entropically favorable because less ordered water molecules

Why does this matter?

• Most small molecule drugs are hydrophobic

• Binding of a drug to a receptor is high entropy because there is less ordered molecules in the receptor pocket

  • The binding of hydrophilic groups is not always better in a protein binding site because polar AAs that interact with these groups may not be oriented to interact any stronger than with solvent water

Measuring hydrophobicity of Molecules

Can be measured experimentally by the use of partition ratios

• Add a test molecule into a mixture of water and an immiscible organic solvent (usually octanol) and measure the concentration of the molecule in the organic vs aqueous phase

• The ratio of the concentrations are reported as the Log P

• Higher Log P = more nonpolar “more greasy” —> less soluble

• Lower Log P = more polar “less greasy” —> more soluble

Pi values

Estimate Log P using data from a variety of reference molecules that provide (group) hydrophobicity values

• An intramolecular hydrogen bond has a positive value

LogD

pH dependent

tells us how much of a drug is ionized at a certain pH

When negative —> Ionized

When neutral —> Log P

When positive —> Unionized

Estimating Total (intrinsic) binding energy

A summation of the independent binding interactions

Relationship between binding energy of a small molecule and equilibrium

Small changes in binding energy can result in large changes in Kd

Large +Kd means it takes a lot of energy for the molecule to dissociate —> Large -Ka

Large +Ka means it takes a lot of energy for the molecule to come together —> Large - Kd

Van Der Waals forces vs H-Bond

Having multiple Van der Waals forces add up in energy and makes the molecule harder to dissociate vs one H-Bond