Drug Discovery (Rajkot)

8/14/2019 Drug Discovery (Rajkot)

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Drug Discovery -Drug Discovery - Thought to Pharmacy Self Thought to Pharmacy Self

Dr. Mahesh ChhabriaDr. Mahesh ChhabriaDept. of Medicinal ChemistryDept. of Medicinal ChemistryL. M. College of PharmacyL. M. College of Pharmacy

Ahmedabad 380 009Ahmedabad 380 009


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Drug DiscoveryDrug Discovery

Discovery of New Chemical Entity (NCE)Discovery of New Chemical Entity (NCE)eliciting desiredeliciting desired

biological responsebiological response

Continuous and ChallengingContinuous and Challenging

Started in 2700 B.C.Started in 2700 B.C.


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Why ?Why ?

To get better and novel drug.To get better and novel drug. Cancer, AIDS, Viral infections, certain CVSCancer, AIDS, Viral infections, certain CVS

disorders till without proper remedies.disorders till without proper remedies. Overcome certain adverse effects of existingOvercome certain adverse effects of existingdrugs. e.g. NSAIDs GI irrtitation; Hdrugs. e.g. NSAIDs GI irrtitation; H 11--receptor antagonists sedation &receptor antagonists sedation &anticholinergic effectsanticholinergic effects


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How ?How ?

Traditional (SAR) approach Traditional (SAR) approach Introduced in 1900Introduced in 1900

Rational approachRational approach Introduced in 1960Introduced in 1960


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Traditional Approach Traditional Approach

Analogue ApproachAnalogue Approach Natural SourceNatural Source

Plant, animal, micro-organisms, marinePlant, animal, micro-organisms, marine Based on serendipity and intuitionBased on serendipity and intuition Based on chemical structure of leadBased on chemical structure of lead

Random screening of large number of Random screening of large number of compoundscompounds Unusual ChemistryUnusual Chemistry


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Traditional Approach Traditional Approach

1.1. Homolog ApproachHomolog Approach2.2. Molecular FragmentationMolecular Fragmentation3.3. Molecular AdditionMolecular Addition4.4. Isosteric replacementIsosteric replacement

S A RS A R


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Outcome ..Outcome ..

Traditional Approach Time consuming, Traditional Approach Time consuming,complex, costly, less productivecomplex, costly, less productive

What is the need of time ?What is the need of time ?Efforts on cutting cost DD by reducingEfforts on cutting cost DD by reducingactual number of compounds to beactual number of compounds to besynthesised and screened and stillsynthesised and screened and still

achieving better success rateachieving better success rate Smarter Drug Design Smarter Drug Design


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Rational ApproachRational Approach

Mechanism based drug designMechanism based drug design Target site / diseased state considered Target site / diseased state considered No importance to chemical structureNo importance to chemical structure Planned synthesis and screeningPlanned synthesis and screening H-bonding, electro negativity values,H-bonding, electro negativity values,

Potential energy, Anchoring sites, Size etc.Potential energy, Anchoring sites, Size etc.are consideredare considered New moleculesNew molecules


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Drug DesignDrug Design

Research tool for novel drug discoveryResearch tool for novel drug discoveryEfforts to develop new drugs onEfforts to develop new drugs on

rational basis so as to decrease therational basis so as to decrease thetrial and error factors and predict thetrial and error factors and predict the

biological activity before theirbiological activity before their

synthesissynthesis


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Drug DesignDrug Design (contd.)(contd.)

Points to be considered Points to be considered 1.1. Geometry of the receptorGeometry of the receptor

2.2. Molecular structure of drugMolecular structure of drug3.3. Behavior of the drug in the biophaseBehavior of the drug in the biophase4.4. Drug-receptor interactionDrug-receptor interaction

5.5. Changes in structure on bindingChanges in structure on binding6.6. Resulting biological responseResulting biological response


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Drug DesignDrug Design (contd.)(contd.)

Multidisciplinary ApproachMultidisciplinary Approach ComputerComputer Medicinal / Organic ChemistryMedicinal / Organic Chemistry Molecular Pharmacology / BiophysicsMolecular Pharmacology / Biophysics Crystallography / SpectroscopyCrystallography / Spectroscopy Biopharmaceutics / PharmacokineticsBiopharmaceutics / Pharmacokinetics


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Path of Drug DiscoveryPath of Drug DiscoveryTarget IdentificationTarget Identification (Data base)(Data base)

Lead IdentificationLead Identification (Data base, MM)(Data base, MM)

Lead GenerationLead Generation (Data base, Reaction files)(Data base, Reaction files)

Lead ModificationLead Modification (Data base, QSAR)(Data base, QSAR)Lead OptimisationLead Optimisation (QSAR)(QSAR)

Lead MoleculeLead MoleculePreclinical andPreclinical and

Clinical trialsClinical trialsOther formalitiesOther formalities

DRUGDRUG


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Drug DesignDrug Design (cont.)(cont.)

TOOLSTOOLS

Molecular modelingMolecular modeling

QSARQSAR


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Molecular ModelingMolecular Modeling

Describes the generation,Describes the generation,manipulation and representation of manipulation and representation of

three dimensional structures of three dimensional structures of molecules and associatedmolecules and associatedphysicochemical propertiesphysicochemical properties


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MM ProcessMM Process

Define Problem (Data base)Define Problem (Data base)

Build MoleculesBuild Molecules

Visualization & CalculationsVisualization & Calculations

Analyze ResultsAnalyze Results


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ContCont Quantum Mechanics:Quantum Mechanics:

Calculation of electronic properties implicated on bothCalculation of electronic properties implicated on bothphysical and chemical properties of molecule with theirphysical and chemical properties of molecule with theirbiological environmentbiological environment

Molecular Mechanics:Molecular Mechanics: Molecular mechanics is a method of calculating theMolecular mechanics is a method of calculating thepotential energy of an isolated molecule or system of potential energy of an isolated molecule or system of interfering molecules.interfering molecules.

Molecular Dynamics:Molecular Dynamics: Molecular dynamics simulations can be used to describeMolecular dynamics simulations can be used to describemany kinds of the events involved in drug-receptormany kinds of the events involved in drug-receptor

interactions, including solvation and conformationalinteractions, including solvation and conformationalchanges required for initial complex formationchanges required for initial complex formation


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Requirements for MMRequirements for MM

Hardware:Hardware: Complicated calculations computer Complicated calculations computer

work station Digital, IBM, Hewlett-work station Digital, IBM, Hewlett-Packard, Silicon GraphicsPackard, Silicon Graphics SoftwareSoftware

As per requirements Modules PCAs per requirements Modules PCbased softwares are Availablebased softwares are Available Accelrys (Discover), Tripos (Sybyl), CCGAccelrys (Discover), Tripos (Sybyl), CCG(MOE)(MOE)


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Types of MM Types of MM

1.1. Direct type of MMDirect type of MMReceptor or structure based MMReceptor or structure based MM

1.1. Indirect type of MMIndirect type of MMChemical structure based MMChemical structure based MM

DockingDocking


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Receptor based MMReceptor based MM


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Indirect type of MMIndirect type of MM


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QSARQSAR

Method to establish quantitativeMethod to establish quantitativerelationship between the descriptorsrelationship between the descriptors

and biological properties of theand biological properties of themoleculesmolecules


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Why QSAR ?Why QSAR ?

Prediction of the biological activityPrediction of the biological activity Classification of compoundsClassification of compounds Optimisation of biological activityOptimisation of biological activity Lead SearchLead Search Reduction in use of animalsReduction in use of animals Minimise random synthesisMinimise random synthesis Economise new drug discoveryEconomise new drug discovery


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Various Methods of QSARVarious Methods of QSAR 1. Free Energy Models1. Free Energy Models

Hansch Model LFERHansch Model LFER Martin & Kubynie Model Non LFERMartin & Kubynie Model Non LFER

2. Free Wilson Mathematical model2. Free Wilson Mathematical model 3. Other statistical Models3. Other statistical Models Discriminant AnalysisDiscriminant Analysis

Principal Component AnalysisPrincipal Component Analysis Factor AnalysisFactor Analysis Cluster AnalysisCluster Analysis

Combined Multivariate AnalysisCombined Multivariate Analysis 4. Pattern Recognition4. Pattern Recognition 5. Topological Method5. Topological Method 6. Quantum Mechanical Methods6. Quantum Mechanical Methods


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Hansch Model -Hansch Model - Random walkRandom walk

KxKx

CC ACAC ResponseResponse

ExtracellularExtracellular Random walkRandom walk Critical reactionCritical reactionPhasePhase sitesite

LL L, StL, St EE L, E,StL, E,St


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Hansch ModelHansch Model

PrinciplePrincipleB.A. B.A. L,L, E,E, StSt

Linear FormLinear FormLog1/c = alogP + bLog1/c = alogP + b + dEs + c+ dEs + c

log1/Clog1/C

PP


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Requirements for QSARRequirements for QSAR

Biological Activity DataBiological Activity Data Large range in observed activity (min. 5Large range in observed activity (min. 5

compounds/ parameter)compounds/ parameter) Identical mode of actionIdentical mode of action Concentration in Molar units (g/kg not suitable)Concentration in Molar units (g/kg not suitable) Activity data as function of concentration, i.e,Activity data as function of concentration, i.e,

EDED5050 , I, I5050 , IC, IC5050 , LD, LD5050 , MIC, MBC etc.., MIC, MBC etc.. Activity data in % i.e. protein binding,Activity data in % i.e. protein binding,

metabolism to be transformed to log.metabolism to be transformed to log.


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Requirements for QSARRequirements for QSAR

Physico-chemical & structuralPhysico-chemical & structuraldiscriptorsdiscriptors

Large range of parameter usedLarge range of parameter used No significant intercorrelation betweenNo significant intercorrelation between

descriptorsdescriptors

About five derivatives per parameterAbout five derivatives per parameter Homogenous distribution in theHomogenous distribution in theparameters used.parameters used.


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Physicochemical ParametersPhysicochemical Parameters

Electronic ParametersElectronic Parameters Experimental ParametersExperimental Parameters

Ionisation ConstantIonisation Constant Pka,Pka, PkaPka Sigma substituent constantSigma substituent constant ,, -,-, +,+, *,*,

= log K = log K RR/log K /log K HH Tafts constant Tafts constant Inductive substituent constantInductive substituent constant

Spectroscopic Chemical ShiftSpectroscopic Chemical Shift IR, NMRIR, NMR Resonance EffectResonance Effect RR Field EffectField Effect FF Ionisation PotetialIonisation Potetial II


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Lipophilic ParametersLipophilic Parameters Partition CoefficientPartition Coefficient log P, (logP)log P, (logP) 22

Pi-substituent coefficientPi-substituent coefficient ,, 22

Rm-Chromatographic parameterRm-Chromatographic parameterRm=log[1/Rf-1)Rm=log[1/Rf-1)

Elution time by HPLCElution time by HPLC log Klog Kcapacity factor K = tr-tcapacity factor K = tr-t 00/t/t 00

SolubilitySolubility


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Stearic ParameterStearic Parameter Tafts steric substituent constant Tafts steric substituent constant EsEs Vandervals dimensionsVandervals dimensions VVww, r, r vv Molecular connectivityMolecular connectivity

= = cij; Cij = 1/cij; Cij = 1/ ii Parachor [P]Parachor [P]

[P] = V[P] = V = M= M /D/D

Chartons steric constantsChartons steric constants Minimal Steric Difference (MSD)Minimal Steric Difference (MSD) Sterimol parametersSterimol parameters


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Data generation andData generation and

AnalysisAnalysis QSAR softwareQSAR software

Biological activity & physicochemical parameter value (dataBiological activity & physicochemical parameter value (database or practical)base or practical)

Regression analysis (simple and multipleRegression analysis (simple and multiple )) Multiple correlation coefficient r , qMultiple correlation coefficient r , q F- testF- test Standard error of estimate - sStandard error of estimate - s

EquationEquation Coefficient of parametersCoefficient of parameters Standard errorStandard error T- test T- test Inter correlation between parameterInter correlation between parameter

Prediction of Biological ActivityPrediction of Biological Activity


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Pharmacokinetics in DrugPharmacokinetics in DrugDiscoveryDiscovery

The activity The activity in vitroin vitro does notdoes notguarantee a sufficientguarantee a sufficient in vivoin vivo effecteffect

~ may be attributed to the PK behavior~ may be attributed to the PK behaviorof drug moleculeof drug moleculePK ProcessesPK Processes

Absorption, Distribution, Metabolism,Absorption, Distribution, Metabolism,EliminationElimination Toxicity Toxicity


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PharmacokineticsPharmacokinetics

What is Pharmacokinetics ?What is Pharmacokinetics ?A Pharmacokinetic model describesA Pharmacokinetic model describes

the change in the amount of drugthe change in the amount of drug(pharmaco) in the body with time(pharmaco) in the body with time(kinetic)(kinetic)


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Structural modification and PK Structural modification and PK

PK consequences expected as a result of PK consequences expected as a result of structural modifications in drugstructural modifications in drug

moleculemolecule1.1. Absorption rateAbsorption rate2.2. Volume of distributionVolume of distribution3.3. Metabolism rateMetabolism rate4.4. Affinity constant for binding to serum proteinsAffinity constant for binding to serum proteins5.5. Rate and type of eliminationRate and type of elimination


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To estimate the influence of small To estimate the influence of smallstructural changes on PKs of a drug can bestructural changes on PKs of a drug can becorrelated with the change in physico-correlated with the change in physico-chemical parameters.chemical parameters.

Quantitative estimation of this correlationQuantitative estimation of this correlationcan be obtained bycan be obtained by

QSPRQSPR


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QSPRQSPR (Quantitative Structure Pharmacokinetic(Quantitative Structure PharmacokineticRelationship)Relationship)

PK PK L,L, E,E, StSt

PK parametersPK parameters1. Absorption rate constant; Ka1. Absorption rate constant; Ka2. Rate constants of metabolism; Km2. Rate constants of metabolism; Km3. Rate constant of elimination; Kel3. Rate constant of elimination; Kel4. Volume of distribution Vd4. Volume of distribution Vd5. Degree of binding to Plasma proteins5. Degree of binding to Plasma proteins


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Advantages of QSAR/QSPRAdvantages of QSAR/QSPR

Help to understand the forces underlyingHelp to understand the forces underlyingthe drug action without knowing thethe drug action without knowing thestructure of receptor involved.structure of receptor involved.

Help to understand factors involved inHelp to understand factors involved intransport, metabolism and excretion of transport, metabolism and excretion of drugs.drugs.

It helps in predicting more potent drugsIt helps in predicting more potent drugswithout synthesizing them. (reduce timewithout synthesizing them. (reduce timeand cost)and cost)


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Disadvantages of Disadvantages of

QSAR/QSPRQSAR/QSPR Insufficient number of compounds andInsufficient number of compounds and

unsatisfactory biological data may lead tounsatisfactory biological data may lead tountrue conclusionsuntrue conclusions

Intercorrelation between two parametersIntercorrelation between two parametersneed to be eliminated.need to be eliminated. Useful for refining a series and not for theUseful for refining a series and not for the

de novode novo research.research. Static and not a dynamic model (2D & notStatic and not a dynamic model (2D & not

3D) 3D-QSAR3D) 3D-QSAR


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Important books forImportant books for

ReferenceReference Comprehensive Medicinal Chemistry, Vol. 4, ed.Comprehensive Medicinal Chemistry, Vol. 4, ed.

C. A. Ramsden, Pragmon Press.C. A. Ramsden, Pragmon Press. Drug Design Vol. 1, ed., E. J. Ariens, AcademicDrug Design Vol. 1, ed., E. J. Ariens, Academic

Press, New York.Press, New York. Bergers Medicinal Chemistry and DrugBergers Medicinal Chemistry and DrugDiscovery, Vol. 1, ed. M. E. Wolff, WilleyDiscovery, Vol. 1, ed. M. E. Wolff, Willeyinterscience Publicationinterscience Publication

Quantitative Drug Design by Y. C. Martin,Quantitative Drug Design by Y. C. Martin,Marcel Dekker Inc., New York.Marcel Dekker Inc., New York.

Journal of Medicinal Chemistry, ACS Publication Journal of Medicinal Chemistry, ACS Publication


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Drug Discovery (Rajkot)

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