This document discusses computer aided drug design (CADD) and the drug discovery process. It describes how CADD uses computational methods to help identify and optimize lead compounds for drug development. The key steps in CADD and drug design include target identification, lead identification through screening libraries of molecules, lead optimization using techniques like docking to improve binding, and preclinical/clinical testing of potential drug candidates. CADD aims to accelerate drug discovery by reducing costs and experiments through in silico methods like structure-based drug design.

1. COMPUTER AIDED DRUG
DESIGN

2. 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.

3. 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.

4. 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

5. 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

6. HITS
LEADS

7. IMPACT OF STRUCTURALIMPACT OF STRUCTURAL
BIOINFORMATICSBIOINFORMATICS
ON DRUG DISCOVERYON 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.

8. 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 targets
and “personalized” targets
Screening up to 100,000 compounds a
day for activity against a target protein
Using a computer to
predict activity
Rapidly producing vast numbers
of compounds
Computer graphics & models help improve activity
Tissue and computer models begin to replace animal testing

9. 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

11. 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

12. 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.

13. 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.

14. 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.

15. 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.

16. • 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

17. 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

18. 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

19. 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.

20. 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

21. • 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

22. 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.

23. 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.

24. MECHANISM OF DRUG ACTION:

25. MECHANISM OF DRUG BINDING:

26. LIGAND BINDING MECHANISM

27. .

28. .

29. .

30. .

31. THE CURRENT ROLES OF THE
COMPUTERIN DRUG DESIGN
• STORING ANDRETRIEVING 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)

32. “DOCKING” COMPOUNDS INTO
PROTEINS COMPUTATIONALLY

33. 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.

34. • 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.

35. 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.

36. 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)

37. EXAMPLES OF OTHERDRUGS
DESIGNEDBY 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)