Drug Design, Discovery and Development

Drug design:
It is a logical effort to design a drug on as much a rational basis as possible thus reducing to the Minimum trial and error approach. It essentially involves the study of biodynamic of a drug besides the interaction between drug molecules and the molecules composing the biological objects (receptors). In short, drug design may be considered as an integrated whole approach which essentially involves various steps, namely: chemical synthesis, evaluation for activity spectrum, toxicological studies, metabolism of the drug, i.e., biotransformation and the study of the various metabolites formed, assay procedures, and lastly galenical formulation and biopharmaceutics. The drug design in a broader sense implies random evaluation of synthetic as well as natural products in bioassay systems, creation of newer drug molecules based on biologically-activeprototypes derived from either plant or animal kingdom (lead compound), synthesis of congeners displaying interesting biological actions, the basic concept of isosterism and bioisosterism, and finally precise design of a drug to enable it to interact with a receptor site Efficaciously.

Drug Discovery:
It is an effort to produce new drug molecules from a lead compound by applying variety of approaches of design. Drug design approach is the prerequisite for drug discovery.

Drug Development:
Drug development is the process of establishing and marketing a biologically active compound obtained by drug design, as a suitable drug by observing pharmacokinetic (ADME), toxicological and clinical parameters.

Stages required in drug discovery and drug Development Drug design and drug discovery
Choose a disease Choose a drug target Identify a bioassay Find a lead compound Isolate and purify the lead compound if necessary Determine the structure of the lead compound Identify structure-activity relationships (SARs) Identify the pharmacophore Improve target interactions

Drug Development
Improve pharmacokinetic properties (ADME) Toxicological evaluation Design a manufacturing process Carry out clinical trials Market the drug Make money!

The discovery and development of a new drug can take 10 years or more, involve the synthesis of over 10,000 compounds and cost in the region of $360 million.

Lead Compound
It is a chemical compound obtained from natural or synthetic sources that possesses a particular biological activity. A lead can be characterized as a compound that has some desirable biological activity, not extremely polar or lipophilic, and not contain toxic or reactive functional groups. Often, molecular weight (<350) and lipophilicity (log P < 3) are considered the most obvious characteristics of a drug-like lead. The lead should also have a series of congeners that modulate biological activity, indicating that further structural modification will improve selectivity and potency.

Drug design can be achieved by exploration of the lead compounds, which involves the search for a new lead or exploitation of the existing leads to produce more active compounds with less toxicity than the original lead compound.

Example:
Sulphanilamide- isolated from the degradation of prontosil or synthesized chemically and acts as antibacterial agent. Lead compound from natural sources: Morphine from opium, cocaine from coca leaves, and quinine from the bark of cinchona tree.

Examples of Natural Products as Leads & Drugs

Cardiac glycosides, morphine, quinine, salicylic acid, taxol, camptothecin, penicillin, cyclosporin A, warfarin, artemisine.

Objective / Aim of drug design strategy

To improve the activity and properties of the lead compound. To improve the binding interactions between a drug and its target, which will increase activity and may also reduce side effects if the improved interactions lead to increased selectivity between different targets.

Principal drug targets:

Receptor Enzyme Nucleic acid

TRADITIONAL DRUG DESIGN (Pharmacophore-based drug design)

Structure-based Drug Design (SBDD) or Target-based approach

A pharmacophore was first defined by Paul Ehrlich in 1909 as "a molecular framework that carries (phoros) the essential features responsible for a drugs (=pharmacon's) biological activity.In 1977, this definition was updated by Peter Gund to "a set of structural features in a molecule that is recognized at a receptor site and is responsible for that molecule's biological activity. The IUPAC definition of a pharmacophore is "an ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target and to trigger (or block) its biological response".

Pharmacophore-based drug design 1. 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.

2. Data collection:
Publications; patents; biological activity; NMR and X-ray data; physiochemical properties to determine the effects of structural changes on activity of drug: structure-activity relationships (SARs)

3. Analysis:
Integrate information about drug (and target) to generate hypothesis about activity. This information will result in the identification of a pharmacophor.

Pharmacophore:
A specific 3D arrangement of chemical groups common to active molecules and essential to their biological activities.

Design new structures

If you know the pharmacophore for your target, you can create new lead compounds based on thepharmacophore! 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.

Approach: Molecular Mimicry

Simple example 1: 3D structures are known 1.

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)

3.

Design new structures:

New molecular mimic will be tested.

Example 2:

(A more typical example) biologically active conformations are not known.

1. Data collection: biological activity. Two molecules below show good activity.

Example 2 (cont): Data collection: Determination of biologically active conformation

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).

Example 2 (cont): Data collection: Determination of biologically active conformation

conformations for each active molecule

Generate low energy

2. Data analysis.

Hypothesis: bioactive conformations share 3D features required for active Superimpose the generated conformations to define a pharmacophore.

Example 2 (cont):
3. Design: Use this pharmacophore to design new molecules to test

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!) Superimposing molecules: dont look at sterics only think of physical properties of molecule.

Pharmacophore-Based Drug Design: Methods Design: use analyzed data to design new compounds hopefully with better properties Four Methods used to design better drugs:
Chemical modification / Molecular modification Database searching De novo Manual These approaches generate more data, which yet again can be used to generate new hypotheses and structures, etc.

Design method 1: Chemical modification Goal: Determine Structure- activity relationships:

What functional groups are important to biological activity?

Design method 1: Chemical modification

Procedure: Alter or remove groups using chemical synthesis and test the activity of the altered molecule (analog). Infer role of those groups in binding.

Consequences of chemical modification to drug activity in addition to altering binding interactions: Metabolism of drug Pharmacokinetics

Molecular modification of lead compound: Formation of Analogues and Prodrugs

Drug design is usually achieved through molecular modification of the lead compound. In the course of drug design the two major types of chemical modifications are achieved through the formation of analogues and prodrugs. An analogue is normally accepted as being that modification which brings about a carbon-skeletal transformation or substituent synthesis. Examples: oxytetracycline, demclocycline, chlortetracycline. The term prodrug is applied to either an appropriate derivative of a drug that undergoes in vivo hydrolysis of the parent drug, e.g., testosteronepropionate, chloramphenicol palmitate and the like; or an analogue which is metabolically transformed to a biologically active drug, for instance: phenylbutazone undergoes in vivo hydroxylation to oxyphenbutazone.

The term prodrug is applied to either an appropriate derivative of a drug that undergoes in vivo hydrolysis of the parent drug, e.g., testosterone propionate, chloramphenicol palmitate and the like; or an analogue which is metabolically transformed to a biologically active drug, for instance: phenylbutazone undergoes in vivo hydroxylation to oxyphenbutazone.

Serendipitous Drug Discovery / Drug discovery by serendipity

The use of nitrous oxide and ether as narcotic gases in surgery resulted from the observation that people who inhaled these chemicals [in parties] did not experience any pain after injury. The vasodilatory activity of amyl nitrite and nitroglycerin was discovered by chemists who developed strong headaches after inhaling or ingesting minor amounts. A wrong working hypothesis on chloral hydrate, which was supposed to degrade metabolically to narcotic chloroform, led to its application as a strong sedative (in reality, the metabolite trichloroethanol is the active form). Similarly, urethane was supposed to release ethanol but is a hypnotic by itself.