1. Drug Discovery and Development
PHG 311
Dr. Mehnaz Kamal 
Assistant Professor
Department of Pharmaceutical Chemistry,
 College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, KSA.
           

3. To Learn the processes of Optimization of the drug
To understand what is Optimization of Lead ?
To know what is Structure Activity Relationships ?
To know Optimization of reactions
To understand the optimising target interactions

4. Lead identification and optimization

5. Lead Identification and Optimization
Synthetic Chemistry
Stages of Drug Discovery
1) Identify target disease
2) Identify drug target
3) Establish testing procedures
4) Find a lead compound (Identification & Optimization)
5) Structure Activity Relationships (SAR)
6) Identify a pharmacophore
7) Drug design- optimising target interactions.
8) Drug design - optimising pharmacokinetic properties.
9) Toxicological and safety tests.
10) Chemical development and production.
11) Patenting and regulatory affairs
12) Clinical trials.

6. Lead Identification and Optimization Synthetic Chemistry
Drug Design: optimizing target interactions
Once the lead compound has been discovered it can be used as the starting point for drug design.
There are various aims in drug design:
The drug should have a good selectivity for its target
The drug should have a good level of activity for its target
The drug should have minimum side effects
The drug should be easily synthesized
The drug should be chemically stable
The drug should have acceptable pharmacokinetics properties
The drug should be non-toxic

7. Lead Identification and Optimization
Synthetic Chemistry
There are two important aspects in drug design and drug strategies to improve :
Pharmacodynamics properties: to optimize the interaction of the drug with its target.
Pharmacokinetics properties: to improve the drug's ability to reach its target & to have acceptable lifetime.
Pharmacodynamics and pharmacokinetics should have equal priority in influencing which strategies are used and which analogues are synthesized.

8. I- Identify target disease
Pharmaceutical companies tend to concentrate on developing drugs for diseases which are prevalent in developed countries, and aim to produce compounds with better properties than existing drugs.
Pharmaceutical companies have to consider economic factors as well as medical ones when they decide which disease to target when designing a new drug.
A huge investment has to be made towards the research and development of a new drug.
Therefore, companies must ensure that they get a good financial return for their investment.

9. I- Identify target disease
As a result, research projects tend to focus on diseases that are important in the developed world, because it is the best market for new drugs.
Thus, research is carried out on ailments such as migraine, depression, ulcers, obesity, flu, cancer and cardiovascular disease.
Less research is carried out on the tropical diseases of the developed world. Only when such diseases start to make an impact in richer countries, the pharmaceutical companies sit up and take notice.
Example: research in antimalarial drugs has increased due to increase in tourism to more exotic countries and the spread of malaria into southern states of US.

10. II- Identify drug target
Choosing which disease to tackle is usually a matter for company’s market strategists. The science becomes important at the next stage.
A molecular target is chosen which is believed to influence a particular disease when affected by a drug.
The greater the selectivity that can be achieved, the less chance of side effects.
Once a therapeutic area has been identified the next stage is to identify a suitable drug target (e.g. receptor, enzyme or nucleic acid)

11. II- Identify a drug target
Understanding which biomacromolecules are involved in a particular disease state is very important.
This will allow the medicinal chemist whether agonist or antagonist to be designed for a particular receptor or whether inhibitors should be designed for a particular enzyme.
For example, tricyclic antidepressants such as Desipramine are known to inhibit the uptake of NA from nerve synapses. However, these drugs also inhibit uptake of serotonin, so the possibility arose that inhibiting serotonin uptake might be beneficial A search for selective serotonin uptake inhibitors has led to the discovery of Fluoxetine, the best selling antidepressant.

12. III- Establish testing procedures
Choosing the right bioassay or test system is crucial to the success of a drug research program.
The test should be simple, quick and relevant as there are usually a large number of compounds to be analyzed.
Human testing is not possible at such early stage, so the test has to be done in vitro first. Because in vitro tests are cheaper, easier to carry out, less controversial and can be automated than in vivo one.
In vivo tests needed to check the drugs interaction with specific target and to monitor their pharmacokinetics properties.

13. IV-Finding a lead compound
A lead compound (i.e. a "leading" compound, not lead metal) in drug discovery is a chemical compound that has pharmacological or biological activity likely to be therapeutically useful, but may still have suboptimal structure that requires modification to fit better to the target. Lead drugs are followed by back-up compounds. Its chemical structure is used as a starting point for chemical modifications in order to improve potency, selectivity, or pharmacokinetic parameters.

14. IV-Finding a lead compound
Once a target and a testing system have been chosen, the next stage is to find a lead compound. A lead compound is a compound which shows the desired pharmaceutical activity.
The level of the activity may not be very great and there may be undesirable side effects.
The lead compound provides a start for the drug design and development process.
There are various ways in which a lead compound might be discovered. However, the following are the ways of discovering the lead compound:
1-Screening of natural products (the plant kingdom, the microbial world, the marine world, animal sources, venoms and toxins)

15. IV-Finding a lead compound
2-Medical folklore
3-Screening synthetic compound “ libraries”
4-Existing drugs (Me too drugs & Enhancing the side effects)
5-Starting from natural ligand or modulator (natural ligands for receptors, natural substrates for enzymes, enzyme products as lead compounds, natural modulators as lead compounds)
6-Combinatorial synthesis
7-Computer aided drug design
8-Serendipity and prepared mind
9-Computerized searching of structural databases
10-Designing lead compounds by NMR

16. 5) Structure Activity Relationships (SAR).
A structure-activity relationship (SAR) is a statement of the effect of structure change on biological activity within a congeneric series (a family) of compounds.
Once the structure of lead compound is known, the medicinal chemist moves on to study its SAR.
The aim is to discover which parts of the molecule are important to biological activity and which are not.
X-ray crystallography and NMR can be used to study and identify important binding interactions between drug and active site.
SAR is synthesizing compounds, where one particular functional group of the molecule is removed or altered.
In this way it is possible to find out which groups are essential and which are not for biological effect

17. 5) Structure Activity Relationships (SAR).
This involves testing all analogues for biological activity and comparing them with the original compound.
If an analogue shows a significant lower activity, then the group that has been modified must be important.
If the activity remain similar, then the group is not essential.
It may be possible to modify some lead compounds directly to the required analogues and other analogues may be prepared by total synthesis.

18. 6) Identify a pharmacophore
sulfanilamide
sulfamethoxazole
sulfadiazine
sulfisoxazole
Sulphonamides
Defines the important groups involved in binding
Defines the relative positions of the binding groups
Need to know Active Conformation
Important to Drug Design
Important to Drug Discovery

19. 6) Identify a pharmacophore
Pharmacophore Selection
Set of structural features in a drug molecule recognized by a receptor. Or
The common denominator shared by a set of active molecules.
Pharmacophoric descriptors are including :
 H-bond sites
Hydrophobic and electrostatic interaction sites
Ring centers and virtual points
 Distances, 3D relationship
Dopamine
Pharmacophore
L = lipophilic site; A = H-bond acceptor;
D = H-bond donor; PD = protonated H-bond donor

20. 7) Drug design - optimization of reactions
Aims:
To optimise the yield and purity of product from each reaction
Notes:
Maximum yield does not necessarily mean maximum purity
May need to accept less than the maximum yield to achieve an acceptable purity
Need to consider cost and safety
Factors:
Temperature, pressure, time, order and rate of addition of reactants and reagents, stirring rate, pH, catalysts, purification procedure

21. 7) Drug design - optimization of reactions
Temperature
Optimum temperature is the temperature at which the rate of reaction is maximised with a minimum of side reactions
Increasing the temperature increases the reaction rate
Increasing the temperature may increase side reactions and increase impurities Compromise is often required:

22. 7) Drug design - optimization of reactions
Pressure
Increased pressure (> 5 kilobar) accelerates reactions where the transition state occupies a smaller volume than the starting materials.
Examples of reactions accelerated by pressure
Esterifications;
amine quaternisation;
ester hydrolysis;
Example:
Esterification of acetic acid with ethanol
proceeds 5 times faster at 2 kbar than at 1 atm.
proceeds 26 times faster at 4 kbar

23. 7) Drug design - optimization of reactions
Solvent:
Important to outcome, yield and purity
Should normally be capable of dissolving reactants and reagents
Insolubility of a product in solvent may improve yields by shifting an equilibrium reaction to its products (but this may be a problem with catalysts).
Should have a suitable boiling point if one wishes to heat the reaction at a constant temperature (heating to reflux)
Should be compatible with the reaction being carried out
Solvents are classed as polar (EtOH, H2O, acetone) or nonpolar (toluene, chloroform)
Polar solvents are classed as protic (EtOH, H2O) or aprotic (DMF, DMSO)
Protic solvents are capable of H-bonding
The polarity and the H-bonding ability of the solvent may affect the reaction

24. 7) Drug design - optimization of reactions
Order and rate of addition of reactants and reagents
Catalysts
• Increase rate at which reactions reach equilibrium
• Classed as heterogeneous or homogeneous
• Choice of catalyst can influence type of product obtained and yield

25. 7) Drug design - optimization of reactions
Order and rate of addition of reactants and reagents
Excess reactant
Shifts equilibrium to products if reaction is thermodynamically controlled
Excess reactant must be cheap, readily available and easily separated from product
May also affect outcome of reaction
Excess diamine is used to increase the proportion of mono-acylated product

26. 7) Drug design - optimization of reactions
Specifications
Specifications define a product’s properties and purity
Properties
Includes melting point, colour of solution, particle size, polymorphism, pH, chemical and stereochemcial purity.
Impurities present are defined and quantified
Residual solvents present are defined and quantified
Acceptable limits are dependent on toxicity (e.g. ethanol 2%, methanol 0.05%)
Carcinogenic impurities must be absent (must not be present in final stage of synthesis).

27. 7) Drug design - optimization of reactions
Specifications
Impurities
Isolate, purify and identify all impurities (HPLC, NMR, mass spectroscopy)
Identify the source of any impurity
Alter the purification at the final stage, the reaction concerned or the reaction conditions.
Impure Reagents / Reactants
Commercially available reagents or reactants contain impurities
Impurities introduced early on in the synthetic route may survive the synthetic route and contaminate the product
An impurity at an early stage of the synthetic route may undergo the same reactions as the starting material and contaminate the final product.

28. 7) Drug design- optimization of reactions
Specifications
Purifications
Introduce a purification to remove any impurities at the end of the reaction sequence or after the offending reaction.
Methods of purification - crystallisation, distillation, precipitation of impurity from solution, precipitation of product from solution.

29. 8) Drug design- optimising target interactions
Aim- To optimise binding interactions with target
Reasons
To increase activity and reduce dose levels
To increase selectivity and reduce side effects
Vary length and bulk of alkyl group to introduce selectivity
Alkyl group in lead compound may interact with hydrophobic region in binding site.
Vary length and bulk of group to optimise interaction
Binding region for N
Receptor 1
Receptor 2