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foreign [Music] topics Channel welcome to the topic uh for M Farm principles of drug Discovery lead optimization so lead compounds discovered in hit to lead process are chemically modified to get a biologically active molecule is called lead optimization lead optimization addresses the pharmacokinetic pharmacodynamic and toxicological issues to improve the clinical utility of the lead compound it is an important step in drug Discovery and development a confirmed lead is used as a starting point and its toxicity potency stability bioavailability and other pharmacokinetic parameters are studied to improve its Target specificity and selectivity to they optimize their leads could be could undergo the further stages for drug development so let us see this example a first one is identification of the lead molecule for the selected Target then modifications in the large lead molecule to increase the drug likeness properties then you are able to optimized lead which could be taken for further stages of drug Discovery this is called lead optimization so in lead optimization an important thing to be considered is identification of pharmacophore so let us take the morphine structure and you have to analyze which functional groups play a role in pharmacokinetics and pharmacodynamics and which is the ring which could not be disturbed to retain its activity that is called a pharmacophoric feature so identification of pharmacophore and other functional groups are very important in lead optimization the let us see an example let us take this as a structure you have the left half and right half suppose these are all assumptions suppose in the left side if they do the modifications that is uh the R Group is given and if you do substitute the R Group with different things so this R Group is substituted with the ch3 c l f and CN and they found that you know when when substituted with f the biological activity is high and in case of the right modification modification in the right side that is R Dash so when the in in case of this R Dash when they substitute with the ch3 they found the biological activity is high so now lead optimization refers to substitution of different functional groups such that you get a optimized lead so this is the concept of lead optimization so let us for lead optimization another refactor which has to be considered which are the groups which can be substituted to increase the drug likeness properties of a lead molecule so they are called bio-isostis they replace uh they retain the activity they alter the toxicity that is reduce the toxicity they improve the kinetic properties are called bio-isostates so the first example is a monovalent groups or atoms many may have same number of atoms valency and they will be steric and electronic configurations one is a monovalent substitutions o h could be substituted with nh2 or ch3 RoR or fluorine the halogens could be substituted Globe instead of chlorine bromine could be substituted or iodine sh si3 are profile tertiary butyl groups can be substituted these are monovalent substitutions and divalence substitutions include a ch2osse that is selenium then NH c o n h r c o s r c o ch2r these are divalent substitutions trivalent substitutions are a double bond CH double bond N double bond p double body as double bond antimony and tetrivalent substitutions are a carbon then silicon quaternary ammonium then phosphorus Arsenic and antimony so let us see the divalent groups or atoms and previously we have seen monovalent atoms or groups so they are C double bond example is here a drug has been given that is total aristat when the substitution of C double bond with yes it gives a drug called total aristat it's aldose reductase inhibitor and in case of C double bond o it is oxotolaristat then another example is a divalent Replacements involving single Bond they can be substituted with nhch2r whoa the non-classical bio isosceles they do not obey the valency are the same number of atoms example is carbonyl group so the carbonyl group can be substituted with different substitutions like so this Guru can be substituted s double Bondo s42 so these have the same configuration as the carbonyl groups so they can be used as bio ISO stairs then another one is the carboxyl group uh it is uh it can be substituted with different functional groups which are mentioned here anything could be substituted to retain the activity so this any of these functional groups could be substituted to retain the property of the carboxyl group so next is amide group so these are the substitutions for amide the TCO nh2 c o n h c double bonds nh2 C double bond och2 like that you can substitute with different substitutions which to retain the activity of the amide group the next is a hydroxyl group hydroxyl group can be substituted with a nhsc double bond r n h2so2r ch2oh NHC double bond o n H2 nhcn rch CN 2. and then the catechol groups can be substituted with these substitutions to retain the activity of the catechol group like adrenaline um a noradrenaline like that then the halogen groups as previously in uh we have seen now the fluorine chlorine bromine can be substituted yes here cf3 could be substituted with CN or NC and twice are CCN Thrice then Tio ether groups can be substituted with a plane ether or a ncn then urea groups could be substituted with these substitutions to retain the property of the Tayo urea group can be substituted with C double bond CN then Benzene group Benzene can be substituted with the pyridine are pyrimidine or thiasol or like that a few run are ASO if you run like that you can you can substitute Benzene with different heterocyclic rings and then pyridine group can be substituted with any Soul or Benzene with the nr3 like that any substitutions to retain the activity of the periodine group is a bio-isoster then a spacer group sometimes you may increase the chain length you may use the ch2 ch2 ch2 like that you can increase the spacing or you may use the Benzene spacing the next is uh we will see some of the examples one is osal Tammy where let us see how lead optimization occurs so the above structure is uh uh let us see this is social Tammy wear and the R Group is this chain length suppose if it gets substituted with a different substitutions we'll see what happens so first case is the r group is substituted with h the influenza A activity is very higher and there is no activity for influenza B so when then the chain length is increased with the ch3 ch2 ch3 then three carbon three carbons then the activity is getting reduced when you increase the chain length then if you see here when the chain length is increased up to six carbons the influenza B activity increases so this depending upon the need the leads could be optimized for the specific biological activity this is example one next is anti-diabetics let us see a lead optimization so this is the sulfonyl urea derivative of anti-diabetics when they are substituted to yield the different this R is R is R1 is substituted and R2 is substituted to yield different anti-diabetic compounds like told butamine chlorpropomide and you can see here when the r 1 is chlorine and the R2 is that is a three chain length three carbons then the half-life increases so this is one of the lead optimization then aldose reductase Inhibitors we have seen a taller stat and the oxotolar is stat let us see the data uh when the this is the group which is going to get substituted here from the table you can understand if it is substituted with double bond yes then the activity uh in vitro as well as in Vivo activity increases so this is also called an lead optimization to get the optimized lead then the next is one for dihydropyridines which are used as anti-anginal drugs or they have anti-hypertensive uses different uses dihydropyridines that is amlodipine been like drugs how they are optimized so this is the lead structure and when the R Group is substituted so here the X group is substituted and you can see from the table when it is substituted with the double bond yes the Vander was radius increases and the ic50 value decreases so this is an example for lead optimization then there are several examples like this let us see the them in a cluster demo prezzle was taken as a lead compound from that uh the compound derived was Omeprazole the race in the isomer of it uh which is available then the derivative valid is optimized to yield a Lansoprazole or a text lansopra Sole and further modifications led to the discovery of pantoprazole which is used as a IV also then it gave rise to um optimizations gave raised to rabi pressle foreign so most of them are used as antipsychotics but the lead compound was a antidepressant then you can see the queen alone antibacterials so here uh these are the substitutions uh as I told uh identification of pharmacophore and the functional groups the lead molecule was norfloxacin and then optimization of it gave rise to your Blockbuster molecule ciprofloxacin and then further optimization led to maxifloxacin and further optimization led to the um the last queen alone derivative which is available in the market is Provo fluxes in then morphine derivatives the lead molecule is a morphine ring optimization of it led to the antagonist morphine antagonist and naloxone and a long-acting argon antagonist Naltrexone which is used for opiate de addiction so this is a classical exam explanation with examples for lead optimization you can practice this memorize this and you can utilize this in the exam point of view I hope it is a useful video thank you for listening happy learning kindly share this to more of your friends kindly if you like it press the like button kindly subscribe to our Pharma topics Channel and go through all the videos which are posted related to your subject thank you