COMPUTER AIDED DRUG DESIGN

DRUG

• A DRUG MAY BE DEFINED AS “A CHEMICAL ENTITY THAT WHEN CONSUMED/INJECTED, RESULTS IN THE CONTROL OR ERADICATION OF A PARTICULAR DISEASE/INFECTION”.

• DRUG DISCOVERY IS A PIPELINE PROCESS INVOLVED IN THE EVOLUTION OF DRUGS AND INVOLVES “GENES TO DRUGS” STRATEGY.

• IDENTIFYING THE GENE RESPONSIBLE FOR A PARTICULAR DISEASE PROCESS AND FINALLY EVOLVING A DRUG TO COMBAT THE DISEASE-THESE THREE FORMS THE MAIN AREAS IN THIS STRATEGY.

COMPUTER AIDED DRUG DESIGN

• DRUG DISCOVERY PROCESS USUALLY STARTS WITH AN ANALYSIS OF BINDING SITES IN TARGET PROTEINS OR AN IDENTIFICATION OF STRUCTURAL FEATURES COMMON TO ACTIVE COMPOUNDS.

• THE PROCESS ENDS WITH THE GENERATION OF SMALL MOLECULE “LEADS” SUITABLE FOR FURTHER CHEMICAL SYNTHETIC WORK.

• IT IS A RECENT AND EMERGING DISCIPLINE THAT USES SEVERAL BIOINFORMATICS TOOLS AND RELATED FIELDS LIKE CHEMI INFORMATICS AND COMBINATORIAL CHEMISTRY.

• CADD USES COMPUTATIONAL CHEMISTRY TO DISCOVER, ENHANCES OR STUDY OF DRUGS AND RELATED BIOLOGICALLY ACTIVE MOLECULES.

ROLE OF CADD

• THE TARGET OF COMPUTER ASSISTED DRUG DESIGN (CADD) IS NOT TO FIND THE IDEAL DRUG BUT TO IDENTIFY AND OPTIMIZE LEAD COMPOUNDS AND SAVE SOME EXPERIMENTS

• THE PARAMETERS EXPECTED FROM A DRUG ARE• SAFETY

• EFFICIENCY

• STABILITY

• SOLUBILITY

• SYNTHETIC VIABILITY

• NOVELTY

HITS LEAD AND DRUGS HITS ARE CHEMICAL COMPOUNDS THAT PRODUCE BIOLOGICAL

ACTIVITY THROUGH TO REPRESENT THERAPEUTIC POTENTIAL.

BIOLOGICAL SCREENING IS CARRIED OUT TO IDENTIFY THOSE COMPOUNDS THAT POSSESS THE BIOLOGICAL ACTIVITY, BETTER THAN THE ‘HITS’. SUCH COMPOUNDS IDENTIFIED ARE CALLED ‘LEADS’

DRUGS ARE SMALL MOLECULES THAT BIND, INTERACT, AND MODULATE THE ACTIVITY OF SPECIFIC BIOLOGICAL RECEPTORS

• THE INITIAL LEADS ARE UNLIKELY TO BE THE FINAL DRUGS. COMPLEX EVALUATIONS ARE NECESSARY AND TYPICALLY THE INITIAL HIT IS MODIFIED ATOM-BY-ATOM TO IMPROVE IMPORTANT AS A CHARACTERISTIC OF THE MOLECULE.

THE CHOICE OF LEAD STRUCTURE IS VERY IMPORTANT FOR SUCCESS IN DRUG DEVELOPMENT.

HITS LEADS

IMPACT OF STRUCTURAL IMPACT OF STRUCTURAL BIOINFORMATICSBIOINFORMATICS

ON DRUG DISCOVERY ON DRUG DISCOVERY

• SPEEDS UP KEY STEPS IN DD PROCESS BY COMBINING ASPECTS OF BIOINFORMATICS, STRUCTURAL BIOLOGY, AND STRUCTURE-BASED DRUG DESIGN

Bio-informatics

Structure-based Drug Design

Structural Biology

Fig 1 & 2

Fauman et al.

Identify disease

Isolate protein

Find drug

Preclinical testing

GENOMICS, PROTEOMICS & BIOPHARM.

HIGH THROUGHPUT SCREENING

MOLECULAR MODELING

VIRTUAL SCREENING

COMBINATORIAL CHEMISTRY

IN VITRO & IN SILICO ADME MODELS

Potentially producing many more targetsand “personalized” targets

Screening up to 100,000 compounds aday for activity against a target protein

Using a computer topredict activity

Rapidly producing vast numbersof compounds

Computer graphics & models help improve activity

Tissue and computer models begin to replace animal testing

DRUG DESIGNING APPROACHES

THERE ARE FOUR BASIC APPROACHES FOR DRUG DESIGNING

1. LIGAND BASED APPROACH

2.TARGET BASED APPROACHES

3.DE NOVO APPROACHES

4.SBDD

LIGAND BASED APPROACH

• THESE ARE USED WHEN THE RECEPTOR IS NOT KNOWN.

• LIGAND BASED APPROACHES TRY TO IDENTIFY CHARACTERISTICS COMMON TO KNOWN LIGANDS TO USE IN SCREENING FOR NEW OR IMPROVED DRUGS.

• IF A SET OF ACTIVE LIGANDS MOLECULES IS KNOWN FOR THE MACROMOLECULAR TARGET, BUT LITTLE OR NO STRUCTURAL INFORMATION EXISTS FOR THE TARGET, LIGAND BASED COMPUTATIONAL METHOD CAN BE EMPLOYED

THERE ARE TWO METHODS TO DO THIS:

1.QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIP(QSAR) METHOD

2.PHARMACOPHORE METHOD

IS THE SPECIFIC 3-D ARRANGEMENT OF FUNCTIONAL GROUPS WITHIN A MOLECULAR FRAMEWORK THAT ARE SPECIFICALLY BIND TO A MACROMOLECULE OR AN ENZYME ACTIVE SITE.

IDENTIFICATION OF A PHARMACOPHORE IS AN IMPORTANT STEP IN THE INTERACTION BETWEEN A RECEPTOR AND A LIGAND.

TARGET BASED APPROACHES

TARGET BASED DRUG DESIGN METHODS BASED ON THE STRUCTURE OF THE BIOLOGICAL TARGET EITHER BOUND OR UNBOUND TO AN INHIBITOR OR SUBSTRATE.

TARGET BASED DESIGN METHODS ARE ALSO KNOWN AS STRUCTURE BASED OR RATIONAL DESIGN METHODS.

DOCKING INVOLVES SCANNING A DATABASE OF KNOWN MOLECULES FOR THOSE LIKELY TO BIND WELL TO THE RECEPTOR.

DOCKING IS USED TO GENERATE POSSIBLE BINDING GEOMETRIES AND CAN EVALUATE USING A SCORING FUNCTION.

THE METHOD MAY ALSO INVOLVE SOME REFINEMENT OF THE INITIALLY GENERATED CONFORMATIONS BEFORE OR AFTER SCANNING.

DE NOVO APPROACHES

• DE NOVO DESIGN IS THE APPROACH TO BUILD A CUSTOMIZED LIGAND FOR A GIVEN RECEPTOR.

• THIS APPROACH INVOLVES THE LIGAND OPTIMIZATION

• LIGAND OPTIMIZATION CAN BE DONE BY ANALYZING PROTEIN ACTIVE SITE PROPERTIES THAT COULD BE PROBABLE AREA OF CONTACT BY THE LIGAND.

• THE ANALYZED ACTIVE SITE PROPERTIES ARE DESCRIBED TO NEGATIVE IMAGE OF PROTEIN SUCH AS HYDROGEN BOND, HYDROGEN BOND ACCEPTOR AND HYDROPHOBIC CONTACT REGION.

STRUCTURE BASED DRUG DESIGN

• STRUCTURE-BASED DRUG DESIGN (SBDD, ALSO KNOWN AS RATIONAL DRUG DESIGN) IS A TECHNIQUE THAT ACCELERATES THE DRUG DISCOVERY PROCESS BY UTILIZING STRUCTURAL INFORMATION TO IMPROVE THE LEAD OPTIMIZATION PROCESS.

• IT HAS BEEN ESTIMATED THAT SBDD CAN REDUCE THE COST FROM TARGET IDENTIFICATION TO INVESTIGATIONAL NEW DRUG(IND) FILLING BY 50%.

• THE TECHNIQUE REQUIRES HIGH RESOLUTION 3-D STRUCTURE OF THE INHIBITOR BOUND TO THE TARGET OBTAINED USING X-RAY CRYSTALLOGRAPHY.

• ONCE THE STRUCTURE IS OBTAINED, THE INTERACTIONS BETWEEN THE INHIBITOR AND THE ACTIVE SITE OF THE TARGET ARE ANALYZED. IMPROVED INHIBITORS RESULT FROM THIS ANALYSIS, RESULTING IN A SHORTENING OF THE LEAD OPTIMIZATION PROCESS.

• RATIONAL DRUG DESIGN IS A METHOD FOR DEVELOPING NEW PHARMACEUTICALS THAT TYPICALLY INVOLVES THE ELUCIDATION OF FUNDAMENTAL PHYSIOLOGICAL MECHANISMS.

• IN THUS COMBINES THE QUEST FOR A SCIENTIFIC UNDERSTANDING OF NATURAL PHENOMENA WITH THE DESIGN OF USEFUL TECHNOLOGY AND HENCE INTEGRATES EPISTEMIC AND PRACTICAL AIMS OF RESEARCH AND DEVELOPMENT.

STEPS INVOLVED IN DRUG DESIGNING

1. TARGET IDENTIFICATION

2. TARGET VALIDATION

3. LEAD IDENTIFICATION

4. LEAD OPTIMIZATION

5. DOCKING

6. PRE CLINICAL TRIALS

7. CLINICAL TRAILS

TARGET IDENTIFICATION

A TARGET IS A MOLECULE(NAMELY A PROTEIN) WHICH IS PRESENT WITHIN AN ORGANISM.

THE APPROACHES OF IDENTIFYING TARGETS INCLUDE PROTEIN EXPRESSION, PROTEIN BIOCHEMISTRY, STRUCTURE FUNCTION STUDIES, STUDY OF BIOCHEMICAL PATHWAYS.

THERE ARE NOW SEVERAL OTHER METHODS TO IDENTIFY SPECIFIC MOLECULAR TARGETS LIKE HIGH THROUGHPUT SEQUENCING ANALYSIS, POSITIONAL CLONING, GENERATION OF CDNA LIBRARIES WITH ESTS AND DATABASE MINING BY SEQUENCE HOMOLOGY.

IT IS IMPORTANT TO DETERMINE WHETHER THE NOVEL TARGETS ARE ACTUALLY RELEVANT TO THE PHYSIOLOGY OF THE DISEASE.

TARGET VALIDATION

AS THERE ARE A PLEOTHORA OF NEW POTENTIAL THERAPEUTIC DRUG TARGETS THAT ARE BEING DISCOVERED, SELECTION AND VALIDATION OF NOVEL MOLECULAR TARGETS HAS BECOME IMPORTANT.

IT NEEDS TO BE CONFIRMED THAT THE TARGETS IDENTIFIED WILL AFFECT AN APPROPRIATE BIOLOGICAL RESPONSE.

TARGETED GENE DISRUPTION (TGD) IS A TERM THAT REFERS TO SEVERAL DIFFERENT METHODS OF TARGET VALIDATION.

LEAD IDENTIFICATION

• A LEAD IS A COMPOUND(USUALLY A SMALL ORGANIC MOLECULE) THAT DEMONSTRATES A DESIRED BIOLOGICAL ACTIVITY ON A VALIDATED MOLECULAR TARGET.

• TO BE TERMED AS A LEAD, THE COMPOUND MUST EXCEED A SPECIFIC POTENCY THRESHOLD AGAINST THE TARGET.

• THE COMPOUNDS USED AS POTENTIAL LEADS CAN BE FROM MANY SOURCES. THE MOST IMPORTANT SOURCES OF LEADS IS LIBRARIES OF MOLECULES LIKE PEPTIDE LIBRARIES, NATURAL COMPOUNDS LIBRARIES ETC.

• SOME OF THE TECHNOLOGIES USED IN THE LEAD IDENTIFICATION

VIRTUAL SCREENING

CHEMOINFORMATICS

PHARMACOPHORE MAPPING

QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIP QSAR

HIGH THROUGHPUT DOCKING

NMR – BASED SCREENING

CHEMICAL GENETICS

LEAD OPTIMIZATION

• ONCE A LEAD COMPOUND IS ESTABLISHED IN THE IDENTIFICATION PROCESS, WE NEED TO OPTIMIZE THE DESIRABLE TRAITS OF THE LEAD

• TO BE CONSIDERED FOR FURTHER DEVELOPMENT , LEAD SHOULD BE AMENABLE FOR CHEMISTRY OPTIMIZATION.

DOCKING

• DOCKING REFERS TO THE ABILITY TO POSITION A LIGAND IN THE ACTIVE OR A DESIGNATED SITE OF A PROTEIN AND CALCULATE THE SPECIFIC BINDING AFFINITIES.

• DOCKING ALGORITHMS CAN BE USED TO FIND LIGANDS AND BINDING CONFORMATIONS AT A RECEPTOR SITE CLOSE TO EXPERIMENTALLY DETERMINED STRUCTURES. DOCKING ALGORITHMS ARE ALSO USED TO IDENTIFY MULTIPLE PROTEINS TO WHICH A SMALL MOLECULE CAN BIND. SOME OF THE DOCKING PROGRAMS ARE GOLD (GENETIC OPTIMIZATION FOR LIGAND DOCKING), AUTODOCK, LUDI, HEX ETC.

MECHANISM OF DRUG ACTION:

MECHANISM OF DRUG BINDING:

LIGAND BINDING MECHANISM

.

.

.

.

THE CURRENT ROLES OF THE COMPUTER IN DRUG DESIGN

• STORING AND RETRIEVING INFORMATION • STRUCTURES DETERMINED BY X-RAY CRYSTALLOGRAPHY FOR

BIOLOGICAL TARGETS (ENZYMES) AND DRUG MOLECULES • MOLECULES AND ACTIVITIES TESTING THE AFFECT OF SMALL

STRUCTURAL CHANGES ON BIOLOGICAL ACTIVITY • INFORMATION ABOUT TOXICITY AND ITS RELATIONSHIP TO

STRUCTURE • VISUALIZING MOLECULES

• SIMILARITIES/DIFFERENCES BETWEEN DRUGS ACTING IN THE SAME WAY

• INTERACTION BETWEEN DRUGS AND RECEPTORS • CALCULATIONS

• INTERACTION STRENGTHS • MOTION (DYNAMICS)

“DOCKING” COMPOUNDS INTO PROTEINS COMPUTATIONALLY

PRE CLINICAL TRAILS

IT IS THE STUDY OF HOW A DRUG MOLECULE INTERACTS WITH ITS MOLECULAR TARGET.

PHARMACOLOGICAL TECHNIQUES ARE EMPLOYED TO STUDY RECEPTOR BINDING, FUNCTIONAL EFFECTS, DOSE RESPONSES ETC.

ADMET CHARACTERISTICS ARE VERY IMPORTANT AT THIS STAGE.

ABSORPTION:- COMPOUNDS ARE DELIVERED BY A RANGE OF ROUTES IN THE BODY. FROM THE SITE OF INITIAL DELIVERY COMPOUNDS WILL BE ABSORBED IN SPECIFIC PATTERNS

DISTRIBUTION:- ONCE ABSORBED COMPOUNDS IS DISTRIBUTED THROUGHOUT THE BODY, IS DETERMINED BY A ROUTE OF ADMINISTRATION AND FORMULATION.

• METABOLISM:- COMPOUNDS ARE METABOLIZED OR MODIFIED BIOLOGICALLY AS THE BODY AIMS TO CLEAR THEM. LIVER IS THE MOST SIGNIFICANT METABOLIC ORGAN OF AN ORGANISM.

• EXCRETION:- COMPOUNDS AND THEIR METABOLITES ARE ELIMINATED FROM THE BODY VIA URINARY, EXHALATION ETC.

• TOXICOLOGY:- MAJORITY OF POTENT DRUGS HAS SIDE EFFECTS LIMITING THE SAFE DOSE WHICH CAN BE USED IN MAN. TOXICOLOGICAL PREDICTIONS MOSTLY PERTAIN TO THE IDENTIFICATION OF STRUCTURAL FEATURES OF DRUG MOLECULES LIKELY TO CONFER TOXICOLOGICAL PROPERTIES.

CLINICAL TRAILS

BEFORE A DRUG IS APPROVED, CLINICAL TRIALS HAVE TO BE FOLLOWED. IT

HAS DISTINCT PHASES:

PHASE 0-> MICRO DOSING OF CANDIDATE TO DETERMINE DISTRIBUTION RELATED INFORMATION

PHASE 1-> FIRST STAGE TESTING IN HUMANS.

PHASE 2-> ACCESS HOW WELL THE DRUG WORKS.

PHASE 3-> MULTICENTER TRIALS ON LARGE PATIENT GROUPS.

PHASE 4-> INVOLVES SAFETY SURVEILLANCE AND ONGOING TECHNICAL SUPPORT OF A DRUG AFTER RECEIVING PERMISSION TO BE SOLD.

SUCCESS STORIES:

• HIV-1 PROTEASE INHIBITORS:

• INVERASE (HOFFMAN-LAROCHE, 1995)

• NORVIR (ABBOT, 1996)

• CRIXIVAN (MERCK, 1996)

• VIRACEPT (AGOURON, 1997)

DRUG DISCOVERY TODAY 2, 261-272 (1997)

EXAMPLES OF OTHER DRUGS DESIGNED BY STRUCTURE-

BASED METHODS:

• HUMAN RENIN INHIBITOR

ANTIHYPERTENSION.

• COLLAGENASE AND STROMELYSIN INHIBITOR ANTICANCER AND ANTIARTHRITIS.

• PURINE NUCLEOTIDE PHOSPHORYLASE INHIBITOR ANTIDEPRESSANT.

• THYMIDYLATE SYNTHASE INHIBITOR ANTIPROLIFERATION.

NATURE 384 SUPPL, 23-26 (1996)