[Music] hello everyone welcome to the course on computer aided drug design we will continue on the topic of for QSAR that is quantitative structure-activity relationship what is this QSAR is just nothing but a mathematical relationship between the biological activity and that's the experimental data or we can collect it from the literature of your molecular system and its geometric physical electronic and chemical property so the dependent variable will be the activity and the independent variable will be a parameter descriptor of structural feature okay it could be a geometric activation descriptor a physical descriptor electronic descriptor or a chemical property so it could be any one of them okay could be any one of them so there are large descriptors available in the literature we will talk about some of them as we go along so basically you are developing a mathematical relation a linear regression or a nonlinear regression so the property or called the independent variables okay or sometimes you call it X and the activity is the dependent variable we call it Y so if you remember your statistics you will get Y is equal to function of radius X's okay so the descriptors could be physical chemical descriptors like you are okay shape size and so on electronic descriptors electronic features staring descriptors volume lipophilic solubility and how lipophilic it is log p hydrogen bonding capabilities okay number of hydrogen bond formation shape charge polarizability so many descriptors thousands and thousands of descriptors can be calculated for a molecule okay we started with the electronic descriptors or a it's also called used by Hammet okay dissociation constant of substituted benzoic acid okay these are called a substituted benzoic acid and these benzoic acid can dissociate okay you have a dissociation constant key and then the dissociate into the acid forms you or edge and okay 0 minus and so on actually okay that is the substitute mineral castle now depending upon the R group and depending upon the position ortho meta para you can have different dissociation constants that's what this table gives as you can see fluorine if it is in the ortho okay ortho it has a very high dissociation constant okay whereas when you go down to ch3 type of group group in the para okay here you can have a very low dissociation constant as you can see right also depending upon the position you can have a and the type of group you can have different dissociation constants okay so electron withdrawing or donating which stabilizes the the anion that is called the anion C whoa whoa - is scalding anyone okay so electron donating groups okay the electron donating groups we have then voyage your own electron donating group whereas electron withdrawing groups we have here X X could be Y okay the chloro bromo I do this you choc voyage Union are these are all electron withdrawing groups acid form is stabilized if R is electron donating so all these groups so this is the acid this is the acid form this is the anion form so the acid form is stabilized when we have electron donating group okay the anion form is stabilized our s electron withdrawing group so if the electron is withdrawn like X and so on you get the anion okay but as acid form is formed when you are getting electron they cause our och3 voyage and so on so if a neon form is stabilized then you're going to have a large K if there is it well established you are going to have a small okay okay so log K a - loke and substituted lock a substituted that is called Sigma okay that's called Sigma so well does all these things come into picture if you look at the antibacterial activity of self and elamite okay these are called self minimize they got a sulfur group and they're from n minus and h plus here okay depending upon the art either you will have this or you will have the anion form the anion form or this form okay but that the anion form is the active antibacterial agent not the neutral form okay because if you look at the para amino benzoic acid but this is which is the substrate for bacteria okay and this drug sulfur drugs also look similar to that so there is a competitive inhibition that's happening and hence the sulfa drugs act okay so the anion form is the active part not the neutral form so that means we need to have this dissociation taking place so depending upon the are like we saw in the position of the are either the anion are the neutral form is stabilized so if you have a really high high Sigma we have very high Sigma okay you have log 1 by C also going up that means that tivity are stabilized at the anion by electron Ventura thus increasing biological activity okay whereas if you have electron donating then the biological activity goes down okay the electron withdrawing we have the logical activity also going up okay now this is with respect to the electronic feature now let's look at the other one and the it's called aesthetic feature if you look at the hydrolysis of esters this is an ester RC Overseers 3r could be anything and hydrolysis means water is acting so you need a catalyst or an enzyme or something like that so it forms our COOH she has three ways that is the methanol okay me tell alcohol so the size of the are affects the rate of reaction because what happens is there is a nucleophilic attack on the carbonyl carbon here so the R okay there is a nucleophilic attack here okay which leads to the formation of our sewage as well as the c3 Voyager so the size of the are tells you how easy is the nucleophilic attack or how difficult it is if the R is very large it's very difficult for the nucleophilic attack so the activity goes down the are easily small activity it goes up this is called steady fricken effect what this is also called Taft parameter and this is calculated by log K of RC whoa whoa ch3 minus log C 3 C over L cos 3 okay now in case the rate constant for ester hydrolysis okay so larger it is okay so we have a larger the our lower will be the rate constant okay where does this important and if you look at acetylcholine esterase there are inhibitors for acetylcholine esterase so hydrolysis of this acetylcholine takes place here okay it attacks your okay so organophosphates must be hydrolyzed to be active and their biological activity depends upon the size of this group this is the living room here okay so the activity is directly proportional to this size of the living room or it's also called a Taft parameter another descriptor which is very very important to see log p that's the latke absorption and distribution process in biological systems are determined by the hydrophilic hydrophobic properties of molecule we looked quite a lot about this log P log P is nothing but in octenol divided by in water a partition of this particular molecule okay more in the octa hole that means we call it hydrophobic lesson octanol more in water we call it hydrophilic so many processes depend and as you can see the I am depending upon the substitution each substitution contributes towards log P for example ch3 is 0.56 that is more hydrophilic if you have a say a tertiary you have 1.98 okay yeah already grew 1.96 c6s 11 2.51 okay whereas if you look at nitro wedge NH 2 the old negative because they are more hydrophilic so if you have a molecule if you substitute with a particular functional group we can find out the contribution and then either subtract the original docu of the parent component I have had a lot P of the parent components okay so log P plays a very important role for example look at anticonvulsant activity of a diver series of drugs this these are the series of drugs you are talking about they have r1 r2 groups here and then we have X here X could be NH c h2o 0 NH 2 okay this is a 5 membered ring so the activity of these drugs these are an anticonvulsant drug okay they all depend upon the log p as you can see more hydrophobic more is the log p activity will be more so lakh people is a very important role we will look at Block B more in detail because it plays a very important role because the absorption through GI depends unlock P as we saw non-impact um so if you look at drugs which bind to serum albumin okay so as the lock P increases because as it becomes more hydrophobic and activity also increases by this is the PSI R this is the regression relation such the log P increases and this is a linear regression in relation as you can see here activity also increases this way it need not be all the time linear okay so greater for hydrophobic drugs okay binding increases as not increases it may not be all the time meaning or it can be like this also there could be an optimum log P log P zero when the activity is Max and initially it increases reaches a Max and then comes down so generally for anesthetic activity of ethers it's followed like this so it's a nonlinear relation so that regression relation could be nonlinear as you can see again it depends on log P but it is log P Square and log P so we have a nonlinear regression relation okay so we have a constant term here and then we have a square term for log P here and then we have a linear term for log P so the relation will go like this it increases initially okay because of this it increases fast as it goes to your large log p value this term starts taking an impact place so the log P starts coming down okay so this is the optimum log P when you have a maximum activity this is supplicant for ethers only anesthetic activity so you can have systems where this type of behaviors may be observed okay so this is called the optimum value anesthetic activity okay so hydrophobicity a place quite a lot actually one thing you need to remember is clear so equations are only applicable come from the same structure of class okay don't forget that I perform a qcr for one class of compounds like benzoic acid and then I try to extend it to some other diorite systems it might not work out okay so for different structural classes also interestingly the optimum lock PE that isn't one here seems to be 2.3 so around that 2.3 you may get very high activity for many of these structural classes also interesting chain structures with lot be around 2.3 enter CNS that is your central nervous system as you remember blood-brain barrier entry we need approximately 2.3 for it to enter if it is lower its hydrophilic so it might not enter at all okay so for many classes of anesthetic drugs even though you may have different types of graphs okay so approximately and the log P comes out to be approximately 2.3 okay this is a very important point you need to keep in mind okay it's very useful you will keep in mind two barbiturates they have a lot be approximately do okay so this number is quite interesting so if you want to avoid you see inner side effects we need to be away from 2 so that it comes either down or down here and so that it doesn't pass the blood-brain barrier okay um so we looked at the electronic effect the constant is called a sigma let's call the Hammett substitution constant okay that is the measure of the electron withdrawing or electron donating influence of substitutions and Sigma for aromatic substitutions measure will be comparing the dissociation constant of substituted benzoic acid with Vince like acid so Sigma is a ratio of you can find out the substituted was tutor okay and the dissociation constant is given by p HC o minus divided by p HC whoa whoa h0 minus means and on-farm Co H is the acid form we have played that long time back okay so the Sigma X we have the electron withdrawing group for example n more - okay the charge is stabilized by X the equilibrium shift to the right okay you freedom shift to the right that is K X is greater than KH KH means some substituted KX I meant substituted so electron withdrawing group okay shifted here K X is greater than K H so this is F Sigma is a positive value okay electron donating group ch3 for example okay so you donating okay then what happens charge is destabilized equilibrium shifts to the left if P briam shifts to the left here okay so K X is less than K H ok so Sigma X will be negative value it's called the Hammad substituted substituent constant okay ok Sigma value depends on inductive and resonance effects okay Sigma depends on whether the substitution is meta or para that's also very important we saw long time back a table where night and para have different values of a dissociation constant our values are invalid due to static effects ortho means its substitutions so close so because of static it might not work actually okay so meta substituent now look at this NW this anymore - okay we have the our here if you have para no.2 Sigma is 0.78 met iron or 2 Sigma is points on one ok and Eve it's drawing inductive effect ok when you have para substitution he withdrawing inductive plus resonance effect because when we have the para substitution we have the there is a resonance that's happening in the nitrogen as you can see and the double bonds in the benzenes keep moving okay like this this is called the resonance effect okay so we have this like this so when the electron is withdrawing you can have with the inductive and resonance effect and that is para substitution okay whereas in meta substitution we will not have the resonance effect happening only the inductive effect will be happening as you can see here when we have all H type of group we saw in no.2 Matar we have a sigma a matter of 0.12 para minus point three seven okay there is only inductive effect whereas electrons withdrawing resonant electron donating the dominant resonant effect inductive effect is my inner so we have resonant effect happening as you can see how the double bond gets shifted shifted shifter okay so you have the lone pairs happening here okay so yeah it's minus point lessor okay what does that mean for the a neutral form is more stable than the onion form here the neutral form is in the metal substitution limit will form is less stable in D and you want form okay and whereas in nitro meta and para almost say die eatle finally four states you have to eat al groups here there are used as essence insecticides we have equations like this to 0.28 to sigma - fine - 0.348 okay so electron withdrawing substitutions increases the activity and so our quantifies a substitutions resonant effect F quantify the substitutions inductive effect okay one is called the resonance the inductive like I showed you here um look at al aliphatic electronic substitutions and that is we have the aliphatic group here so you can have high hydrolysis like this aliphatic so we have a amine or H is the height how does they act they are defined by again Sigma one you have only purely inductive effects and they are obtained experimentally by measuring the rates of hydrolysis of aliphatic esters okay hydrolysis rays measured under basic and acidic conditions so you do not have the resonance happening here you will always have induction happening here because unless the aromatic where we have the resonant bonds aliphatic will not have it so X electron donating rate goes down because Sigma 1 is negative next electron withdrawing rate goes up because Sigma 1 is positive okay understand so in aliphatic systems there is only inductive effect there is no resonance effect we can make how do you measure we can measure by looking at the rates of hydrolysis of aliphatic esters hydrolysis is measured under basic and acidic condition so if you have electron donating then we have the rate going down if you have electron withdrawing pulling rate goes up so basic under basic conditions if affected by stearic like I mentioned stearic plus electronic factors so gives Sigma 1 after correction for still effect under acidic conditions rate affected by C steric factors only that is yes we talked about years before right that size factor so remember that other basic conditions will have static and electronic effect under acidic conditions we have only static effect that is why here we mentioned is Sigma L here because you can have static effect also coming into the picture Stila factors Taft's steric factor we talked about its compared the rates of hydrolysis of substituted aliphatic still against standard ester under acidic conditions okay if you bring basic then you are going to have a some electronic effect coming into okay so we can have a KX man log of K X minus log of K 0 K R K X represents the rate of hydrolysis of a substituted ester rate of hydrolysis of the parent ester okay limited to substitutions which interacts directly with the tetrahedral transition state for the reaction remember that cannot be used for substituent switch interact with the transition state by resonance or hydrogen bonding so yeah they will start interfering the time the resonance effect and hydrogen bonding all these will affect you are tapped parameter may undervalue these steric effect of groups in an intramolecular process that is not binding to a receptor sort of situation you also have a term called molar refractivity it's a measure of substituent's volume this is a descriptor which we can calculate what's called molar reflectivity is given by n square minus 1 divided by n square minus 2 molecule rate by density okay this is a correction factor this is called the index of refraction correction factor for polarization that's called index of refraction so it's a function of molecule rate and she not density that's called a molar reflectivity when you do molecular weight be density of course you end up with volume right so this is a descriptor which we use many times then comes hands equation what is handsy USTR equation relating various physical chemical properties in the biological activity of a series of composition so you will have log p coming into picture electronic factors coming into picture steric factor okay so we can have your aqueous AR activity on the left hand side which may have terms related to electronic steric and not B so you start with a simple equation and you can elaborate it as more structures are synthesized and now P you can put it as a parabolic relation x-ray so log p spy ROP electronic term stick factor this is a constant so typical hands equation okay remember QSAR and we can develop only when we have some experimental data for activity that's the left hand side or we get some data from literature where someone else has estimated the activity for a series of component okay so look at this adrenergic blocking activity of beta hello okay this data hello Peter Aaron I mean these are immense okay array elements as you can see here okay we have the nitrogen here but that's why we call it the parallel amines then we have the hollow compounds here so typically this is all the hands equation looks like okay 1.2 to minus 1.5 to 2 pi minus 1 point fine and Sigma Phi represents the hydrophobicity Sigma represents the electronic okay so it's a positive with respect to the hydrophobic substituent and it's negative with respect to the electronic factor that is electron donating substituent's this called an has question so the log p related term comes here the electronic comes here but there is no mention much about steric information here these are anti-malarial activity of phenanthrene amino carbonyls okay so we have three fused benzene rings okay we have the amino group here that's well I mean no carbonyls your because we have the white here look at them we have the log p square rock P okay then comes the hydrophobic part of it and then we have the electronic part of it okay we have two terms one for Sigma X and Sigma Y similarly for the PI X n I pi Y activity increases slightly as well being parabolic relation optimum value for luck p-value for activity activity increases for hydrophobic substituent's especially in ring wife yeah sure and then activating Reese's electron withdrawing substitution - friendly ring wife I think it's being is on fire you electronic yeah and what okay [Music] substitutes will be chosen to satisfy the following criteria the range of values for each physical chemical properties studied okay so when I synthesize new molecules I will try to substitute so that I get a different and file that means a different hydrophobic hydrophilic values I get different Sigma's and so on values must not be correlated for different properties that means they must be orthogonal in value at least five structures are required for each parameter studied for this is a very important rule of thumb okay for each parameter studied so for example I'm looking at a different I am substituting with H ome or a tail or M profile and riptile so the file changes like this so for H 0 so it becomes more hydrophobic hydrophobic okay molarity if activity changes like this I defined what is mother activity before okay correlated values so we have substituted and H Emmy Emmy Phi M R as you can see some of them there is no correlation here okay there is no correlation in these values these are all as they are all correlated i M R an D PI there is something called a crane plot which is also used in QSAR okay this is a creek plot okay what is this we have our two things happening one is the PI we have on the x-axis okay bye that is the hydrophobic hydrophilic city of the substitution Sigma is the electronic the substitution positive Sigma positive 5 this is negative pi negative Sigma okay so different substitution groups as you can see you know two Falls here it's got a very high electronic and very low pipe if you look at fluoro very very low Sigma and PI if you look at the SF Files alphabet Phi fluorines it's got high pi as well as reasonably high Sigma okay so this is electron withdrawing so here we have the electron donating your small hydrophobic yeah it's more hydrophilic so if you have a say c c whoa whoa H it's a hydrophilic okay it's a hydrophilic and then it's also electron withdrawing if you look here this is a hydrophilic Oh H and it's electron donating so this is a very interesting fellow so we can't decide which substituent to put it into our parent molecule for our studies do I want to look at electron withdrawing effect by maintaining the hydrophobic hydrophilic balance or do I want to have modifying the hydrophobic hydrophilic activity nature by maintaining the electron the Sigma so by deciding I can synthesize different types of molecules and study their activity and so that I have a very fruitful and QSAR relationship that's very very important so what is called allow an easy identification of suitable substance for a qsn analysis which includes both the Sigma and the pipe choose a substituent from each quadrant two inch I'll ensure orthogonality that's very important to substituent with a range of values for each property okay so and I can choose a substituent safe from our groups here I can choose from here I can choose from bottom I can choose from this that way I will really keep orthogonality and also I can choose one low one high one low and high so I can get the range also into the picture okay range of values so that's the advantage of that particular figure then we have something called the topple scheme okay which can help you to synthesize molecule in a very very effective way so that you address both the hydrophobicity as well as the the electron features that is electron withdrawing and electron donating features okay so we will continue this table scheme in the next class okay thank you very much for your time [Music] [Music]