1 What is QSAR A QSAR is a

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What is QSAR? A QSAR is a mathematical relationship between a biological activity of a molecular system and its geometric and chemical characteristics. QSAR attempts to find consistent relationship between biological activity and molecular properties, so that these “rules” can be used to evaluate the activity of new compounds. 2

STERIC PARAMETERS stearic features of drug markedly effect the drug receptor interactions reflecting the change In onset and duration of biological action. eg: buprenorphine As it is more lipophilic it enters CNS more rapidly , rapid onset and duration of action, because of bulky substituent's it needs time to orient in favorable confirmation and bulky substituent's also delays detachment of drug from receptor. This leads to late onset and duration of action. Various steric parameters in qsar are 1. Tafts steric constant 2. Molecular connectivity index 3. Sterimol 4. parachor 3

Taft Equation The Taft equation is a linear free energy relationship (LFER) used in physical organic chemistry in the study of reaction mechanisms and in the development of quantitative structure activity relationships for organic compounds. It was developed by Robert W. Taft in 1952 as a modification to the Hammett equation. While the Hammett equation accounts for how field, inductive, and resonance effects influence reaction rates, the Taft equation also describes the steric effects of a substituent. The Taft equation is written as: where log(ks/k. CH 3) is the ratio of the rate of the substituted reaction compared to the reference reaction σ* is the polar substituent constant that describes the field and inductive effects of the substituent, Es is the steric substituent constant, ρ* is the sensitivity factor for the reaction to polar effects δ is the sensitivity factor for the reaction to steric effects. 4

Polar Substituent Constants, σ*: q. Polar substituent constants describe the way a substituent will influence a reaction through polar (inductive, field, and resonance) effects. q. To determine σ* Taft studied the hydrolysis of methyl esters (RCOOMe). q. The hydrolysis of esters can occur through either acid and base catalyzed mechanisms, both of which proceed through a tetrahedral intermediate. q In the base catalyzed mechanism the reactant goes from a neutral species to negatively charged intermediate in the rate determining (slow) step, while in the acid catalyzed mechanism a positively charged reactant goes to a positively charged intermediate. 5

However, because of the difference in charge buildup in the rate determining steps it was proposed that polar effects would only influence the reaction rate of the base catalyzed reaction since a new charge was formed. He defined the polar substituent constant σ* as: Where q log(ks/k. CH 3)B is the ratio of the rate of the base catalyzed reaction compared to the reference reaction. q log(ks/k. CH 3)A is ratio of a rate of the acid catalyzed reaction compared to the reference reaction. q ρ* is a reaction constant that describes the sensitivity of the reaction series. q The factor of 1/2. 48 is included to make σ* similar in magnitude to the Hammett σ values. 6

Steric Substituent Constants, Es : Taft thus assumed that steric effects would influence both reaction mechanisms equally. Due to this, the steric substituent constant Es was determined from solely the acid catalyzed reaction, as this would not include polar effects. Es was defined as: where ks is the rate of the studied reaction and k. CH 3 is the rate of the reference reaction (R = methyl). δ is a reaction constant that describes the susceptibility of a reaction series to steric effects. 7

Polar Sensitivity Factor, ρ* : Similar to ρ values for Hammett plots, the polar sensitivity factor ρ* for Taft plots will describe the susceptibility of a reaction series to polar effects. When the steric effects of substituents do not significantly influence the reaction rate the Taft equation simplifies to a form of the Hammett equation: The polar sensitivity factor ρ* can be obtained by plotting the ratio of the measured reaction rates (ks) compared to the reference reaction (k. CH 3) versus the σ* values for the substituents. • If ρ* > 1, the reaction accumulates negative charge in the transition state and is accelerated by electron withdrawing groups. • If 1 > ρ* > 0, negative charge is built up and the reaction is mildly sensitive to polar effects. • If ρ* = 0, the reaction is not influenced by polar effects. • If 0 > ρ* > -1, positive charge is built up and the reaction is mildly sensitive to polar effects. • If -1 > ρ*, the reaction accumulates positive charge and is accelerated by electron donating groups. 8

Molar refractivity: qproposed by pauling and pressman. qrepresents size and polarizibility of molecule or it is measure of both volume of compound and how it is easily polarized. qit characterizes bulk of molecule or substituent but not shape. MR= n 2 -1/n 2+2. MW/d MW= molecular weight N= index of refraction at 200 c d=density of compound at 200 c 9

q. THE greater the positive MR value of substituent the larger its steric or bulk effect and substituent binds to polar surface while a negative value indicates steric hinderance at binding site. q. The use of MR terms in some ligand – enzyme interactions could be interpreted with help of 3 D structures in Qsar. substituent MR values H 0. 0 CH 3 4. 7 C 2 H 5 9. 4 C 6 H 5 24. 3 OH 1. 5 NH 2 4. 2 SO 2 NH 2 11. 3 10

Molecular connectivity index (χ): q. It indicates branching index in the given structure. q. MC describes molecular substructures in topological terms. q. It is concept based on molecular structure but doesn’t take account of molecular properties. Since branched isomers of molecule differ in properties with unbranched ones. q. Correlation of physicochemical properties with no. of atoms and also upon arrangement of atoms. q. MCI (χ) helps to quantify the effect of size and shape on biological response. q MCI represents substructure environment, degree of branching, unsaturation, hetero atoms and their position and presence of cyclic structure. 11

Parachor: It is a steric parameter which is defined as molar volume V which has been corrected forces of intermolecular attraction by multiplying with the fourth root of surface tension. P = γ 1/4 * M / d M = molecular weight d = density Corections to parachor: Pr = 0. 012 Pr if to be used for non polar compounds. Pr = 0. 012 Pr – 0. 6 if to be used for compounds containing a phenolic OH or phenolic ether function. Pr = 0. 012 Pr – 1. 2 if to be used for compounds containing carbonyl, ester, amine, nitrile, alcoholic or aliphatic ether functions. 12

Minimal Steric Difference: the most active structure that fits receptor is termed as standard (s). Then the planar structural formulae's of other molecules are superimposed on standard neglecting small differences between bond lengths and bond angles then the number of non-superimposable atoms give MSD value for considered structure since it is the only portion which doesn’t overlap. Eg: phenyl and cyclohexyl. 13

Lipophilic parameters include partition coefficient, chromatographic parameters, π substitution constant, chromatographic parameters. These parameters define partitioning of compound between the aqueous and non aqueous phase. 2 parameters are commonly used to represent lipophilicity which are partition coefficient (P): which refers to whole molecule π substitution constant: refers to substituted groups. partition coefficient (P): It is ratio of concentration of substance in organic and aqueous phase under equilibrium conditions It represents drug distribution between an organic and aqueousphase. partition coefficient (P): 14

For easily ionisable drug: P = [Drug]octanol/[Drug]water * 1/ (1 -α) Where α = degree of ionisation Generally for the determination of partition coefficient n- octanol --- water system is used qn- octanol is used because of similarity with biological cell membrane system having long alkyl chain and polar hydroxyl groups. q. Having low vapour pressure. q. Uv transparent over large range of wavelengths. 15

q. If compound is more soluble in water then log p is negative. q If compound is more soluble in octanol then log p is positive. more positive log p more lipophilic. qif P reaches infinity which means C 12 micelles are formed and drug will not cross aqueous phase. 16

π substitution constant or lipophilic substitution constant or hydrophobic substitution constant : π is the effect of a given substituent on log p of basic skeleton. π = log Px – PH where Px = P of Molecule carrying substituent X. PH= P of unsubstituted compound. Eg: π cl = log P chlorobenzene – log P benzene = 2. 84 – 2. 13 = o. 71 q. The value of π for the compound is sum of π values of each of separate substituent's. q. The π value of specific substituent varies with structural environment of substituent and they are highly position dependent so that π is different for different positions (O, M and P). q + ve π value indicates substituent has high lipophilicity than H and drug favours organic phase. q – ve π value indicates substituent has low lipophilicity than H and drug favours aqueous phase. 17

Hydrophobic Fragmentation Constant(f) : According to the π substitution constant the value of hydrogen is zero and no difference between π CH 3 and π CH 2 , but the lipophilic contribution of hydrogen atom is not zero hence rekker suggested a new system called hydrophobic fragmentation constant(f) which is measure of absolute lipophilicity contribution of corresponding group or substituent. (f) For some substituents substituent (f) aromatic (f) Aliphatic H 0. 175 CH 3 0. 702 CH 2 0. 530 NH 2 – 0. 854 – 1. 428 COOH – 0. 093 – 0. 954 18

Example of calculation of log P of benzene = 2. 5 (parent compound) fi of methyl = 0. 6 fi or aromatic fluorine = -0. 4 Fi for fluorine atom ortho to a methyl group is -0. 3 log P= 2. 5 + 0. 6 + (-0. 4) + (-0. 3) = 2. 4 19

Cl Benzene (Log P = 2. 13) Chlorobenzene (Log P = 2. 84) p. Cl = 0. 71 CONH 2 Benzamide (Log P = 0. 64) p. CONH 2= -1. 49 20

Chromatographic parameters: RM value calculated from RP-TLC as alternative lipophilic parameter in qsar. RM= log (1/Rf - 1) Disadvantage: chromatographic behaviour of drug is not identical to drug partitioning in biological system. 21

Hansch analysis: Two stages of drug action was proposed based on 1. A random walk from point of administration to the site of which involves passage over series of membranes and is therefore related to partition coefficient. 2. Attachment for the receptor site which depends on shape of molecule hence stereochemistry of substituent groups electron density on attachment groups. He suggested linear and non- linear dependence of biological activity on different parameters like π, σ and ES. example of a linear equation where multiple variables are used to obtain a correlation with biological activity (1/c). ------ linear equation Where c is molar concentration that elicits a constant biological response 22

π= lipophilic substitution constant. σ= hammet constant. ES = tafts steraic constant. ------ parabolic equation Example of an extended Hansch Equation where the Taft steric parameter, Es, has been included. q. Practically all the parameters used in hansch analysis are linear free energy related so it is known as linear free energy approach or extra thermodynamic approach 23

Not all parameters are necessarily significant in a qsar model for biological activity. to derive an equation following rules are formulated by hansch. q Selection of independent variables like log p, π, σ, MR , steric parameters should be tried for obtaining best equation where the inter correlation coefficient should be larger than 0. 6 -0. 7. q All reasonable parameters must be validated by appropriate statistical procedure by stepwise regression analysis. Applications: q to predict the activity of an as yet unsynthesised compound. q To give an indication of the importance of influence of parameters on mechanism by which drug acts. q Applied to various problems in order to correlate the biological activity with chemical structure. q Hansch analysis serves as guide in future testing and synthesis of new compound and to play roles of hydrophobic, electronic and stearic factors in drug receptor interaction. 24

Advantages of Hansch analysis A) Use of descriptors (p, s, Es etc. ) from small organic molecules may be applied to biological systems. B) Predictions are quantitative and may be evaluated statistically. C) Quick and easy. D) Potential extrapolation: conclusions reached may be extended to chemical substituent's not included in the original analysis. 25

Disadvantages of Hansch analysis A) Descriptors required for substituent's being studied. B) Large number of compounds required (training set for which physicochemical parameters and biological activity is available). C) Limitations associated with using small molecule descriptors, such as steric factors, on biological systems (i. e. descriptors from physical chemistry). D) Partial protontation of drugs at physiological conditions (can be included in mathematical model). E) Extrapolations beyond the values of descriptors used in the study are limited. F) Correlation between physical descriptors. For example, the hydrophobicity will have some correlation with the size and, thus, the Taft steric term. 26

Topliss Scheme Used to decide which substituents to use if optimising compounds one by one (where synthesis is complex and slow) Completely non mathematical and non statistical which doesn’t need computerization of data. Example: Aromatic substituents 27

Craig Plot Craig plot shows values for 2 different physicochemical properties for various substituents Example: +s -p -p -s -p +s +p +p -s +p 28

Free-Wilson Approach Method • The 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 substituents BA = μ + Σ ai. J Where μ =contribution of unsubstituted compounds Σ ai. J =contribution of substituted compounds I =No. of position the substituent occurs J =No. of substituent at that position Activity = k 1 X 1 + k 2 X 2 +. …kn. Xn + Z • Xn 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 n • Z is a constant representing the overall activity of the structures studied 29

Free-Wilson Approach Advantages • No need for physicochemical constants or tables like π, σ etc • Useful for structures with unusual substituents • Useful for quantifying the biological effects of molecular features that cannot be quantified or tabulated by the Hansch method Disadvantages • A 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 activity • The effects of different substituents may not be additive (e. g. intramolecular interactions) 30

CADD METHODS: Quantum mechanics: It is based on assumption that electrons and all material particles exhibit wave like properties. the mathematical approach of wave mation is applied to electrons, atomic and molecular structure. It is based on Schrödinger wave equation Hψ = E ψ= total potential and kinetic energy of all particles in the same structure. Ψ= wave function, H = hamiltonium operatoracting on wave function. Applications: q. Quantum mechanics calculations can be used for energy minimisation studies. q. Wave function can be used to calculate a range of chemical properties like electrondensity, dipolemoment, energies and positions of orbitals. q. For calculating bond dissosciation energies, electrostatic potentials, heat of formation for specific confirmations. 31

MOLECULAR MECHANICS: q. MAINly for the study of molecular modelling. q. Here the position of nuclei is determined by force of attraction and repulsion operating in that structure. q. Total Potential energy of molecule is given by sum of all energies of attractive and repulsive forces between atoms in structure. E total = Σ Estretching +ΣEbending+ ΣEtorsion+ ΣEVd. W+ ΣEcolumbic Estretching = ½ k(r – r 0)2 Ebending: ½Kθ(θ – θ 0)2 r = ideal bond r 0 = standerd bond K = force constant θ 0= ideal bond length 32

Etorsion = ½ K Φ (1+ COS (m( Φ + Φ offset) Φ = torsion angle K Φ= energy barrier to the rotation about torsion angle Φ m= periodicity of rotation Φ offset = ideal torsion angle. EVd. W = ε [(rmin)12/r – 2 (rmin/r)6] (rmin/r) 6 = represents attractive force [(rmin)12/r = represents repulsive force. r= actual distance between atoms. ε = energy Ecolumbic = qiqj/Drij qiqj= point charges on atoms I and j , rij = distance between atoms, D =dielectric constant 33

REFERENCE: qcomprehensive medicinal chemistry --- volume 4 --- Corwin Hansch. q. Principles of medicinal chemistry --- volume 1 --- Kadam. q. Medicinal chemistry --- 3 rd edition --- Thomas Nogrady. q. Organcic chemistry of drug design and drug action --- silverman. q. Medicinal chemistry --- volume 2 --- Ilango. q. Molecular modeling in drug design ---Berger. 34

Thank you 35