Quantitative Structure Activity Relationships QSAR and 3D-QSAR Chapter 18.

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Quantitative Structure Activity Relationships QSAR and 3D-QSAR Chapter 18

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Transcript of Quantitative Structure Activity Relationships QSAR and 3D-QSAR Chapter 18.

  • Slide 1
  • Quantitative Structure Activity Relationships QSAR and 3D-QSAR Chapter 18
  • Slide 2
  • Introduction AimsAims To relate the biological activity of a series of compounds to their physicochemical parameters in a quantitative fashion using a mathematical formulaTo relate the biological activity of a series of compounds to their physicochemical parameters in a quantitative fashion using a mathematical formula RequirementsRequirements Quantitative measurements for biological and physicochemical propertiesQuantitative measurements for biological and physicochemical properties Physicochemical PropertiesPhysicochemical Properties Hydrophobicity of the moleculeHydrophobicity of the molecule Hydrophobicity of substituentsHydrophobicity of substituents Electronic properties of substituentsElectronic properties of substituents Steric properties of substituentsSteric properties of substituents Most common properties studied
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  • Hydrophobicity of the Molecule Partition Coefficient P = [Drug in octanol] in octanol] [Drug in water] High P High hydrophobicity
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  • Activity of drugs is often related to PActivity of drugs is often related to P e.g. binding of drugs to serum albumin (straight line - limited range of log P) Binding increases as log P increasesBinding increases as log P increases Binding is greater for hydrophobic drugsBinding is greater for hydrophobic drugs Log1C 0.75 logP 0.75 logP+ 2.30 2.30 Hydrophobicity of the Molecule Log (1/C) Log P......... 0.78 3.82
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  • Example 2 General anaesthetic activity of ethers (parabolic curve - larger range of log P values) Optimum value of log P for anaesthetic activity = log P o Log1C - 0.22(logP) 2 + 1.04 logP 1.04 logP+ 2.16 2.16 Hydrophobicity of the Molecule Log P o Log (1/C)
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  • QSAR equations are only applicable to compounds in the same structural class (e.g. ethers) However, log P o is similar for anaesthetics of different structural classes (ca. 2.3)However, log P o is similar for anaesthetics of different structural classes (ca. 2.3) Structures with log P ca. 2.3 enter the CNS easilyStructures with log P ca. 2.3 enter the CNS easily (e.g. potent barbiturates have a log P of approximately 2.0) (e.g. potent barbiturates have a log P of approximately 2.0) Can alter log P value of drugs away from 2.0 to avoid CNS side effectsCan alter log P value of drugs away from 2.0 to avoid CNS side effects Hydrophobicity of the Molecule Notes :
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  • Hydrophobicity of Substituents - the substituent hydrophobicity constant ( ) Notes : A measure of a substituents hydrophobicity relative to hydrogenA measure of a substituents hydrophobicity relative to hydrogen Tabulated values exist for aliphatic and aromatic substituentsTabulated values exist for aliphatic and aromatic substituents Measured experimentally by comparison of log P values with log P of parent structureMeasured experimentally by comparison of log P values with log P of parent structure Example: Positive values imply substituents are more hydrophobic than HPositive values imply substituents are more hydrophobic than H Negative values imply substituents are less hydrophobic than HNegative values imply substituents are less hydrophobic than H Benzene (LogP = 2.13) = 2.13) Chlorobenzene (LogP = 2.84) = 2.84) Benzamide (LogP = 0.64) = 0.64) ClCONH 2 Cl = 0.71 CONH = -1.49 2
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  • Notes: The value of is only valid for parent structuresThe value of is only valid for parent structures It is possible to calculate log P using valuesIt is possible to calculate log P using values A QSAR equation may include both P and .A QSAR equation may include both P and . P measures the importance of a molecules overall hydrophobicity (relevant to absorption, binding etc)P measures the importance of a molecules overall hydrophobicity (relevant to absorption, binding etc) identifies specific regions of the molecule which might interact identifies specific regions of the molecule which might interact with hydrophobic regions in the binding site Hydrophobicity of Substituents - the substituent hydrophobicity constant ( ) Example: meta-Chlorobenzamide Cl CONH 2 Log P (theory) = log P (benzene) + Cl + CONH = 2.13 + 0.71 - 1.49 = 2.13 + 0.71 - 1.49 = 1.35 = 1.35 Log P (observed) = 1.51 2
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  • Electronic Effects Hammett Substituent Constant ( ) Hammett Substituent Constant ( ) Notes: The constant ( ) is a measure of the e-withdrawing or e-donating influence of substituentsThe constant ( ) is a measure of the e-withdrawing or e-donating influence of substituents It can be measured experimentally and tabulatedIt can be measured experimentally and tabulated (e.g. for aromatic substituents is measured by comparing the dissociation constants of substituted benzoic acids with benzoic acid) X=H K H = Dissociation constant Dissociation constant= [PhCO 2-] [PhCO 2 H]
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  • X= electron withdrawing group (e.g. NO 2 ) X = log logKX K H = logK logK X - H Charge is stabilised by X Equilibrium shifts to right K X > K H Positive value Hammett Substituent Constant ( ) Hammett Substituent Constant ( )
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  • X= electron donating group (e.g. CH 3 ) X = log logKX K H = logK logK X - H Charge destabilised Equilibrium shifts to left K X < K H Negative value Hammett Substituent Constant ( ) Hammett Substituent Constant ( )
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  • NOTES : value depends on inductive and resonance effects value depends on whether the substituent is meta or para ortho values are invalid due to steric factors Hammett Substituent Constant ( ) Hammett Substituent Constant ( )
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  • meta-Substitution EXAMPLES: p (NO 2 ) m (NO 2 ) e-withdrawing (inductive effect only) e-withdrawing (inductive + resonance effects) Hammett Substituent Constant ( ) Hammett Substituent Constant ( ) para-Substitution
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  • m (OH) p (OH) e-withdrawing (inductive effect only) e-donating by resonance more important than inductive effect Hammett Substituent Constant ( ) Hammett Substituent Constant ( ) EXAMPLES: meta-Substitution para-Substitution
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  • QSAR Equation: Diethylphenylphosphates(Insecticides) log1C 2.282 2.282 - 0.348 0.348 Conclusion: e-withdrawing substituents increase activity Hammett Substituent Constant ( ) Hammett Substituent Constant ( )
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  • Electronic Factors R & F Electronic Factors R & F R - Quantifies a substituents resonance effectsR - Quantifies a substituents resonance effects F - Quantifies a substituents inductive effectsF - Quantifies a substituents inductive effects
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  • Aliphatic electronic substituents Defined by IDefined by I Purely inductive effectsPurely inductive effects Obtained experimentally by measuring the rates of hydrolyses of aliphatic estersObtained experimentally by measuring the rates of hydrolyses of aliphatic esters Hydrolysis rates measured under basic and acidic conditionsHydrolysis rates measured under basic and acidic conditions X= electron donating Rate I = -ve X= electron withdrawing Rate I = +ve Basic conditions: Rate affected by steric + electronic factors Gives I after correction for steric effect Acidic conditions: Rate affected by steric factors only (see E s )
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  • Steric Factors Steric Factors Tafts Steric Factor (E s ) Measured by comparing the rates of hydrolysis of substituted aliphatic esters against a standard ester under acidic conditionsMeasured by comparing the rates of hydrolysis of substituted aliphatic esters against a standard ester under acidic conditions E s = log k x - log k o k x represents the rate of hydrolysis of a substituted ester k o represents the rate of hydrolysis of the parent ester Limited to substituents which interact sterically with the tetrahedral transition state for the reactionLimited to substituents which interact sterically with the tetrahedral transition state for the reaction Cannot be used for substituents which interact with the transition state by resonance or hydrogen bondingCannot be used for substituents which interact with the transition state by resonance or hydrogen bonding May undervalue the steric effect of groups in an intermolecular process (i.e. a drug binding to a receptor)May undervalue the steric effect of groups in an intermolecular process (i.e. a drug binding to a receptor)
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  • Steric Factors Steric Factors Molar Refractivity (MR) - a measure of a substituents volume MR= (n2-1) (n 2 -2) x mol. wt. density Correction factor for polarisation (n=index of refraction) Defines volume
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  • Steric Factors Steric Factors Verloop Steric Parameter - calculated by software (STERIMOL) - gives dimensions of a substituent - can be used for any substituent - can be used for any substituent L B 3 B 4 B4B4 B3B3 B2B2 B1B1 Example - Carboxylic acid
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  • Hansch Equation Hansch Equation A QSAR equation relating various physicochemical properties toA QSAR equation relating various physicochemical properties to the biological activity of a series of compounds the biological activity of a series of compounds Usually includes log P, electronic and steric factorsUsually includes log P, electronic and steric factors Start with simple equations and elaborate as more structures areStart with simple equations and elaborate as more structures are synthesised synthesised Typical equation for a wide range of log P is parabolicTypical equation for a wide range of log P is parabolic Log 1 C - k (logP) 2 + k 2 logP logP+ k 3 + k 4 E s + k 5 1
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  • Hansch Equation Hansch Equation Log1C 1.22 1.22 - 1.59 1.59 + 7.89 7.89 Conclusions: Activity increases if is +ve (i.e. hydrophobic substituents)Activity increases if is +ve (i.e. hydrophobic substituents) Activity increases if is negative (i.e. e-donating substituents)Activity increases if is negative (i.e. e-donating substituents) Example: Adrenergic blocking activity of -halo- -arylamines
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  • Conclusions: Activity increases slightly as log P (hydrophobicity) increases (note that the constant is only 0.14)Activity increases slightly as log P (hydrophobicity) increases (note that the constant is only 0.14) Parabolic equation implies an optimum log P o value for activityParabolic equation implies an optimum log P o value for activity Activity increases for hydrophobic substituents (esp. ring Y)Activity increases for hydrophobic substituents (esp. ring Y) Activity increases for e-withdrawing substituents (esp. ring Y)Activity increases for e-withdrawing substituents (esp. ring Y) Log1C - 0.015 (logP) 2 + 0.14 logP 0.14 logP+ 0.27 0.27 X + 0.40 0.40 Y + 0.65 0.65 X + 0.88 0.88 Y + 2.34 2.34 Hansch Equation Hansch Equation Example: Antimalarial activity of phenanthrene aminocarbinols
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  • Substituents must be chosen to satisfy the following criteria; A range of values for each physicochemical property studiedA range of values for each physicochemical property studied Values must not be correlated for different properties (i.e. they must be orthogonal in value)Values must not be correlated for different properties (i.e. they must be orthogonal in value) At least 5 structures are required for each parameter studiedAt least 5 structures are required for each parameter studied Correlated values. Are any differences due to or MR? No correlation in values Valid for analysing effects of and MR. Hansch Equation Hansch Equation Substituent H Me Et n-Pr n-Bu 0.00 0.56 1.02 1.50 2.13 MR 0.10 0.56 1.03 1.55 1.96 Substituent H Me OMe NHCONH 2 I CN 0.00 0.56 -0.02 -1.30 1.12 -0.57 MR 0.10 0.56 0.79 1.37 1.39 0.63 Choosing suitable substituents
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  • Craig Plot Craig Plot Craig plot shows values for 2 different physicochemical properties for various substituents Example : -- ++ - + + + - - + -
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  • Allows an easy identification of suitable substituents for a QSAR analysis which includes both relevant propertiesAllows an easy identification of suitable substituents for a QSAR analysis which includes both relevant properties Choose a substituent from each quadrant to ensure orthogonalityChoose a substituent from each quadrant to ensure orthogonality Choose substituents with a range of values for each propertyChoose substituents with a range of values for each property Craig Plot Craig Plot
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  • Topliss Scheme Topliss Scheme Used to decide which substituents to use if optimising compounds one by one (where synthesis is complex and slow) Example: Aromatic substituents
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  • Rationale Replace H with para-Cl (+ and + ) + and/or + advantageous Favourable unfavourable + and/or + disadvantageous Act. Littlechange Act. Add second Cl to increase and further Replace with OMe (- and - ) Replace with Me (+ and - ) Further changes suggested based on arguments of and steric strain Topliss Scheme Topliss Scheme
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  • Aliphatic substituents
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  • Topliss Scheme Topliss Scheme Example
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  • Example
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  • Bio-isosteres Bio-isosteres Choose substituents with similar physicochemical properties ( e.g. CN, NO 2 and COMe could be bio-isosteres)Choose substituents with similar physicochemical properties ( e.g. CN, NO 2 and COMe could be bio-isosteres) Choose bio-isosteres based on most important physicochemicalChoose bio-isosteres based on most important physicochemical property property (e.g. COMe & SOMe are similar in p ; SOMe and SO 2 Me are similar in ) -0.55 0.40-1.58-1.63-1.82-1.51 p 0.50 0.84 0.49 0.72 0.57 0.36 m 0.38 0.66 0.52 0.60 0.46 0.35 MR11.221.513.713.516.919.2
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  • Free-Wilson Approach Free-Wilson Approach The biological activity of the parent structure is measured and compared with the activity of analogues bearing different substituentsThe biological activity of the parent structure is measured and compared with the activity of analogues bearing different substituents An equation is derived relating biological activity to the presence or absence of particular substituentsAn equation is derived relating biological activity to the presence or absence of particular substituents Activity = k 1 X 1 + k 2 X 2 +.k n X n + Z X n is an indicator variable which is given the value 0 or 1 depending on whether the substituent (n) is present or notX n is an indicator variable which is given the value 0 or 1 depending on whether the substituent (n) is present or not The contribution of each substituent (n) to activity is determined by the value of k nThe contribution of each substituent (n) to activity is determined by the value of k n Z is a constant representing the overall activity of the structures studiedZ is a constant representing the overall activity of the structures studied Method
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  • Free-Wilson Approach Free-Wilson Approach No need for physicochemical constants or tablesNo need for physicochemical constants or tables Useful for structures with unusual substituentsUseful for structures with unusual substituents Useful for quantifying the biological effects of molecular features that cannot be quantified or tabulated by the Hansch methodUseful for quantifying the biological effects of molecular features that cannot be quantified or tabulated by the Hansch method Advantages Disadvantages A large number of analogues need to be synthesised to represent each different substituent and each different position of a substituentA large number of analogues need to be synthesised to represent each different substituent and each different position of a substituent It is difficult to rationalise why specific substituents are good or bad for activityIt is difficult to rationalise why specific substituents are good or bad for activity The effects of different substituents may not be additiveThe effects of different substituents may not be additive (e.g. intramolecular interactions)
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  • Free-Wilson / Hansch Approach Free-Wilson / Hansch Approach It is possible to use indicator variables as part of a Hansch equation - see following Case StudyIt is possible to use indicator variables as part of a Hansch equation - see following Case Study Advantages
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  • Case Study Case Study QSAR analysis of pyranenamines (SK & F) (Anti-allergy compounds )
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  • Stage 1 19 structures were synthesised to study and C Log1 -0.14 - 1.35( 1.35( ) 2 0.72 0.72 and = total values for and for all substituents Conclusions: Activity drops as increasesActivity drops as increases Hydrophobic substituents are bad for activity - unusualHydrophobic substituents are bad for activity - unusual Any value of results in a drop in activityAny value of results in a drop in activity Substituents should not be e-donating or e-withdrawing (activity falls if is +ve or -ve)Substituents should not be e-donating or e-withdrawing (activity falls if is +ve or -ve) Case Study Case Study
  • Slide 38
  • Stage 2 61 structures were synthesised, concentrating on hydrophilic substituents to test the first equation Anomalies a) 3-NHCOMe, 3-NHCOEt, 3-NHCOPr. Activity should drop as alkyl group becomes bigger and more hydrophobic, but the activity is similar for all three substituents b) OH, SH, NH 2 and NHCOR at position 5 : Activity is greater than expected c) NHSO 2 R : Activity is worse than expected d) 3,5-(CF 3 ) 2 and 3,5(NHMe) 2 : Activity is greater than expected e) 4-Acyloxy : Activity is 5 x greater than expected Case Study Case Study
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  • a) 3-NHCOMe, 3-NHCOEt, 3-NHCOPr. Possible steric factor at work. Increasing the size of R may be good for activity and balances out the detrimental effect of increasing hydrophobicity b) OH, SH, NH 2, and NHCOR at position 5 Possibly involved in H-bonding c) NHSO 2 R Exception to H-bonding theory - perhaps bad for steric or electronic reasons d) 3,5-(CF 3 ) 2 and 3,5-(NHMe) 2 The only disubstituted structures where a substituent at position 5 was electron withdrawing e) 4-Acyloxy Presumably acts as a prodrug allowing easier crossing of cell membranes. The group is hydrolysed once across the membrane. Case Study Case Study Theories
  • Slide 40
  • Stage 3 Alter the QSAR equation to take account of new results Log1C -0.30 - 1.35( 1.35( ) 2 + 2.0(F 2.0(F-5)+ 0.39(345 0.39(345 -HBD)-0.63(NHSO 2 ) + 0.78(M - V)V)V)V)+ 0.72(4 0.72(4-OCO)- 0.75 0.75 Conclusions (F-5) Electron-withdrawing group at position 5 increases activity (based on only 2 compounds though) (3,4,5-HBD) HBD at positions 3, 4,or 5 is good for activity Term = 1 if a HBD group is at any of these positions Term = 1 if a HBD group is at any of these positions Term = 2 if HBD groups are at two of these positions Term = 2 if HBD groups are at two of these positions Term = 0 if no HBD group is present at these positions Term = 0 if no HBD group is present at these positions Each HBD group increases activity by 0.39 Each HBD group increases activity by 0.39 (NHSO 2 ) Equals 1 if NHSO 2 is present (bad for activity by -0.63). Equals zero if group is absent. (M-V) Volume of any meta substituent. Large substituents at meta position increase activity 4-O-CO Equals 1 if acyloxy group is present (activity increases by 0.72). Equals 0 if group absent Case Study Case Study
  • Slide 41
  • Stage 3 Alter the QSAR equation to take account of new results Log1C -0.30 - 1.35( 1.35( ) 2 + 2.0(F 2.0(F-5)+ 0.39(345 0.39(345 -HBD)-0.63(NHSO 2 ) + 0.78(M - V)V)V)V)+ 0.72(4 0.72(4-OCO)- 0.75 0.75 Note The terms (3,4,5-HBD), (NHSO 2 ), and 4-O-CO are examples of indicator variables used in the free-Wilson approach and included in a Hansch equation Case Study Case Study
  • Slide 42
  • Stage 4 37 Structures were synthesised to test steric and F-5 parameters, as well as the effects of hydrophilic, H-bonding groups Anomalies Two H-bonding groups are bad if they are ortho to each other Explanation Possibly groups at the ortho position bond with each other rather than with the receptor - an intramolecular interaction Case Study Case Study
  • Slide 43
  • Stage 5 Revise Equation NOTES a) Increasing the hydrophilicity of substituents allows the identification of an optimum value for ( = -5). The equation is now parabolic (-0.034 ( ) 2 ) optimum value for ( = -5). The equation is now parabolic (-0.034 ( ) 2 ) b) The optimum value of is very low and implies a hydrophilic binding site c) R-5 implies that resonance effects are important at position 5 d) HB-INTRA equals 1 for H-bonding groups ortho to each other (act. drops -086) equals 0 if H-bonding groups are not ortho to each other equals 0 if H-bonding groups are not ortho to each other e) The steric parameter is no longer significant and is not present Log1C -0.034( ) 2 -0.33 + 4.3(F 4.3(F-5)+ 1.3 (R 1.3 (R-5)- 1.7( 1.7( ) 2 + 0.73(345 0.73(345-HBD) - 0.86 (HB 0.86 (HB-INTRA)- 0.69(NHSO 0.69(NHSO 2 )+ 0.72(4 0.72(4-OCO)- 0.59 0.59 Case Study Case Study
  • Slide 44
  • Stage 6 Optimum Structure and binding theory Case Study Case Study NH 3 X X X XH
  • Slide 45
  • NOTES on the optimum structure It has unusual NHCOCH(OH)CH 2 OH groups at positions 3 and 5It has unusual NHCOCH(OH)CH 2 OH groups at positions 3 and 5 It is 1000 times more active than the lead compoundIt is 1000 times more active than the lead compound The substituents at positions 3 and 5The substituents at positions 3 and 5 are highly polar,are highly polar, are capable of hydrogen bonding,are capable of hydrogen bonding, are at the meta positions and are not ortho to each otherare at the meta positions and are not ortho to each other allow a favourable F-5 parameter for the substituent at position 5allow a favourable F-5 parameter for the substituent at position 5 The structure has a negligible ( 2 valueThe structure has a negligible ( 2 value Case Study Case Study
  • Slide 46
  • 3D-QSAR 3D-QSAR Physical properties are measured for the molecule as a wholePhysical properties are measured for the molecule as a whole Properties are calculated using computer softwareProperties are calculated using computer software No experimental constants or measurements are involvedNo experimental constants or measurements are involved Properties are known as FieldsProperties are known as Fields Steric field - defines the size and shape of the moleculeSteric field - defines the size and shape of the molecule Electrostatic field - defines electron rich/poor regions of moleculeElectrostatic field - defines electron rich/poor regions of molecule Hydrophobic properties are relatively unimportantHydrophobic properties are relatively unimportant Notes Advantages over QSAR No reliance on experimental valuesNo reliance on experimental values Can be applied to molecules with unusual substituentsCan be applied to molecules with unusual substituents Not restricted to molecules of the same structural classNot restricted to molecules of the same structural class Predictive capabilityPredictive capability
  • Slide 47
  • 3D-QSAR 3D-QSAR Comparative molecular field analysis (CoMFA) - TriposComparative molecular field analysis (CoMFA) - Tripos Build each molecule using modelling softwareBuild each molecule using modelling software Identify the active conformation for each moleculeIdentify the active conformation for each molecule Identify the pharmacophoreIdentify the pharmacophore Method Active conformation Build 3D model Define pharmacophore
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  • 3D-QSAR 3D-QSAR Comparative molecular field analysis (CoMFA) - TriposComparative molecular field analysis (CoMFA) - Tripos Build each molecule using modelling softwareBuild each molecule using modelling software Identify the active conformation for each moleculeIdentify the active conformation for each molecule Identify the pharmacophoreIdentify the pharmacophore Method Active conformation Build 3D model Define pharmacophore
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  • 3D-QSAR 3D-QSAR Place the pharmacophore into a lattice of grid pointsPlace the pharmacophore into a lattice of grid points Method Each grid point defines a point in spaceEach grid point defines a point in space Grid points.....
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  • 3D-QSAR 3D-QSAR Method Each grid point defines a point in spaceEach grid point defines a point in space Grid points..... Position molecule to match the pharmacophorePosition molecule to match the pharmacophore
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  • 3D-QSAR 3D-QSAR A probe atom is placed at each grid point in turnA probe atom is placed at each grid point in turn Method Probe atom = a proton or sp 3 hybridised carbocationProbe atom = a proton or sp 3 hybridised carbocation..... Probe atom
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  • 3D-QSAR 3D-QSAR A probe atom is placed at each grid point in turnA probe atom is placed at each grid point in turn Method Measure the steric or electrostatic interaction of the probe atomMeasure the steric or electrostatic interaction of the probe atom with the molecule at each grid point..... Probe atom
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  • 3D-QSAR 3D-QSAR The closer the probe atom to the molecule, the higher the steric energyThe closer the probe atom to the molecule, the higher the steric energy Define the shape of the molecule by identifying grid points of equal steric energy (contour line)Define the shape of the molecule by identifying grid points of equal steric energy (contour line) Favorable electrostatic interactions with the positively charged probe indicate molecular regions which are negative in natureFavorable electrostatic interactions with the positively charged probe indicate molecular regions which are negative in nature Unfavorable electrostatic interactions with the positively charged probe indicate molecular regions which are positive in natureUnfavorable electrostatic interactions with the positively charged probe indicate molecular regions which are positive in nature Define electrostatic fields by identifying grid points of equal energy (contour line)Define electrostatic fields by identifying grid points of equal energy (contour line) Repeat the procedure for each molecule in turnRepeat the procedure for each molecule in turn Compare the fields of each molecule with their biological activityCompare the fields of each molecule with their biological activity Identify steric and electrostatic fields which are favorable or unfavorable for activityIdentify steric and electrostatic fields which are favorable or unfavorable for activity Method
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  • 3D-QSAR 3D-QSAR Method CompoundBiologicalSteric fields (S)Electrostatic fields (E) activity at grid points (001-998) at grid points (001-098) S001S002S003S004S005 etcE001E002E003E004E005 etc 15.1 26.8 35.3 46.4 56.1 Tabulate fields for each compound at each grid point Partial least squares analysis (PLS) QSAR equation Activity = aS001 + bS002 +..mS998 + nE001 +.+yE998 + z.....
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  • 3D-QSAR 3D-QSAR Define fields using contour maps round a representative moleculeDefine fields using contour maps round a representative molecule Method
  • Slide 56
  • 3D-QSAR CASE STUDY 3D-QSAR CASE STUDY Tacrine Anticholinesterase used in the treatment of Alzheimers disease
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  • 3D-QSAR CASE STUDY 3D-QSAR CASE STUDY Conclusions Large groups at position 7 are detrimental Groups at positions 6 & 7 should be electron-withdrawing No hydrophobic effect Conventional QSAR Study 12 analogues were synthesised to relate their activity with the hydrophobic, steric and electronic properties of substituents at positions 6 and 7 C Log1 pIC pIC 50 = - 3.09 MR(R 1 )+ 1.43F(R 1.43F(R 1,R 2 )+ 7.00 7.00 Substituents: CH 3, Cl, NO 2, OCH 3, NH 2, F (Spread of values with no correlation)
  • Slide 58
  • 3D-QSAR CASE STUDY 3D-QSAR CASE STUDY CoMFA Study Analysis includes tetracyclic anticholinesterase inhibitors (II) Not possible to include above structures in a conventional QSAR analysis since they are a different structural classNot possible to include above structures in a conventional QSAR analysis since they are a different structural class Molecules belonging to different structural classes must be aligned properly according to a shared pharmacophoreMolecules belonging to different structural classes must be aligned properly according to a shared pharmacophore
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  • 3D-QSAR CASE STUDY 3D-QSAR CASE STUDY Possible Alignment Overlay Good overlay but assumes similar binding modes
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  • 3D-QSAR CASE STUDY 3D-QSAR CASE STUDY A tacrine / enzyme complex was crystallised and analysed Results revealed the mode of binding for tacrine Molecular modelling was used to modify tacrine to structure (II) while still bound to the binding site (in silico) The complex was minimized to find the most stable binding mode for structure II The binding mode for (II) proved to be different from tacrine X-Ray Crystallography
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  • 3D-QSAR CASE STUDY 3D-QSAR CASE STUDY Analogues of each type of structure were aligned according to the parent structure Analysis shows the steric factor is solely responsible for activity Blue areas - addition of steric bulk increases activity Red areas - addition of steric bulk decreases activity Alignment
  • Slide 62
  • 3D-QSAR CASE STUDY 3D-QSAR CASE STUDY Prediction 6-Bromo analogue of tacrine predicted to be active (pIC 50 = 7.40) Actual pIC 50 = 7.18