Drug Design, Discovery and Development

Drug design, sometimes referred to as rational drug design or more simply rational design, is the inventive process of finding new medications based on the knowledge of a biological target. The drug is most commonly an organic small molecule that activates or inhibits the function of a biomolecule such as a protein (receptor or enzyme), which in turn results in a therapeutic benefit to the patient. In the most basic sense, drug design involves the design of small molecules that are complementary in shape and charge to the biomolecular target with which they interact and therefore will bind to it.

What is really meant by drug design is ligand design (i.e., design of a small molecule that will bind tightly to its target). Although modeling techniques for prediction of binding affinity are reasonably successful, there are many other properties, such as bioavailability, metabolic half-life, lack of side effects, etc., that first must be optimized before a ligand can become a safe and efficacious drug.

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-active-prototypes derived from either plant or animal kingdom (lead compound), synthesis of congeners displaying interesting biological actions by different approaches of molecular modifications and finally precise design of a drug to enable it to interact with a receptor site efficaciously.

Drug design frequently but not necessarily relies on computer modeling techniques. This type of modeling is often referred to as computer-aided drug design. Finally, drug design that relies on the knowledge of the three-dimensional structure of the biomolecular target is known as structure-based drug design.

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 diseaseChoose a drug target Identify a bioassayFind a ‘lead compound’ Isolate and purify the lead compound if necessaryDetermine the structure of the lead compound Identify structure-activity relationships (SARs) Identify the pharmacophore Improve target interactions

Drug Development

Improve pharmacokinetic properties (ADME)Toxicological evaluationDesign a manufacturing processCarry out clinical trialsMarket the drugMake 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: i. Sulphanilamide- isolated from the degradation of prontosil or

synthesized chemically and acts as antibacterial agent. ii. Lead compound from natural sources: Morphine from opium,

cocaine from coca leaves, and quinine from the bark of cinchona tree.

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: i. Receptor ii. Enzyme iii. Nucleic acid

TRADITIONAL DRUG DESIGN (Pharmacophore-based drug design)

Lead generation: Natural ligand / Screening

Biological Testing

Synthesis of New Compounds by molecular modification of leads

Drug Design CycleDrug Design CycleIf promising

Pre-Clinical Studies

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

Molecular Biology & Protein Chemistry

3D Structure Determination of Target and Target-Ligand Complex

Modelling

Structure Analysisand Compound Design Biological Testing

Synthesis of New Compounds

If promising

Pre-Clinical Studies

Drug Design CycleDrug Design Cycle

Natural ligand / Screening

A pharmacophore was first defined by Paul Ehrlich in 1909 as "a molecular framework that carries (phoros) the essential features responsible for a drug’s (=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 medicineNatural ligand Drug already known Computer-aided drug designComputerized 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 pharmacophore…

Pharmacophore-Based Drug Design: Methods

Four Methods used to design better drugs:

Chemical modification / Molecular modification

Database searching

De novo (from the beginning) approach

Manual

These approaches generate more data, which yet again can be used to generate new hypotheses and structures, etc.

Design method: Chemical modification

Goal: Determine Structure- activity relationships to know what functional groups are important to biological activity.

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 drugpharmacokinetics

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.

OH O OHOHO O

NH2

OHN(CH3)2ClH3C OH

Chortetracycline

OH O OHOH

O O

NH2

OHN(CH3)2H3C OHOH

Oxytetracycline

OH O OHOHO O

NH2

OHN(CH3)2Cl H OH

Demeclocycline

OH O OHOHO O

NH2

OHN(CH3)2H3C OH

156

78

HH

Tetracycline

Activity: against wide range of gram-positive and gram-negative bacteria including rickettsia, Mycoplasma etc.

Examples of drug design through the formation of analogues

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 oxyphenylbutazone.

N

N

Phenylbutazone

N

N

O

O

Oxyphenylbutazone

N

NHCH2CH2C

HO

H3C

Phenylbutazone alcohol

(Better tolerated than phenylbutazone)

(uricosuric agent)

Antirheumatic drug

n-C4H9

O

O

n-C4H9

O

O

OH

Serendipitous drug discovery

"Serendipity" in drug discovery implies the finding of one thing while looking for something else i.e. accidental discovery or discovery by chance.

The discovery of penicillin's and sulfonamides as the antibiotics and antibacterial agents respectively are the suitable examples serendipitous drug discovery.

Serendipitous Discovery of Chlordiazepoxide (Librium) without a Lead

In 1955 Roche set out to prepare a series of benzheptoxadiazines as potential new tranquilizer drugs, but the actual structure was found to be that of a quinazoline 3-oxide.

2.4

NO

N

R2

R1

X

Y

2.5

+-N

N R1

OR2

X

Y

No active compounds were found, so the project was abandoned.

In 1957, during a lab cleanup, a vial containing what was thought to be the latter compound (X = 7-Cl, R1 = CH2NHCH3, R2 = C6H5) was sent for testing, and it was highly active.

Further analysis showed that the actual structure of the compound was the benzodiazepine 4-oxide (chlordiazepoxide HCl), Librium (the first benzodiazepine) presumably produced in an unexpected reaction of the corresponding chloromethyl quinazoline 3-oxide with methylamine.

N

N CH2Cl

OClN

HN NHCH3

OCl

CH2Cl

CH3NH2

NCH2

NNHCH3

ClCl

OH

N

N CH2NHCH3

OCl

..

-+

-+

-+

..

2.6

CH3NH2

N

N

Cl

NHCH3. HCl

O

chlordiazepoxide HCl2.3

+-