Springer.Free.Energy.Calculations.in.Rational.Drug.Design.(Springer.2001)

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1、Chapter1HistoricalOverviewandFutureChallengesJ.AndrewMcCammonHowardHughesMedicalInstitute,DepartmentofChemistryandBiochemistry,andDepartmentofPharmacology,UniversityofCalifornia,SanDiego,LaJoIIa,CA92093I.INTRODUCTIONTheselectivebindingofmoleculestoformproductivecomplexesisofcentralim

2、portancetopharmacologyandmedicinalchemistry.Althoughkineticfactorscaninfluencetheyieldsofdifferentmolecularcomplexesincellularandothernon-equilibriumenvironments,1theprimaryfactorsthatonemustconsiderintheanalysisofmolecularrecognitionarethermodynamic.Inparticular,theequilibriumconsta

3、ntforthebindingofmoleculesAandBtoformthecomplexABdependsexponentiallyonthestandardfreeenergychangeassociatedwithcomplexation.Ithaslongbeenrecognizedthatifonecouldcomputethestandardfreeenergychangeofcomplexationofbiologicallyactivemolecules,itwouldbepossiblebothtogainadeeperunderstand

4、ingoftheoriginsofmolecularrecognitioninbiology,andtocontemplatethe"firstprinciples"designofPharmaceuticalsandothercompounds.Suchcalculationswereattempted,forexample,bytheScheragagroupasearlyas1972,2althoughlimitationsincomputerpowerdidnotallowinclusionofsolvationorentropiceffectsinth

5、iswork.In1986,WongandMcCammon3combinedthestatisticalmechanicaltheoryoffreeenergywithatomisticsimulationsofsolventandsolutestocalculatetherelativestandardfreeenergyofbindingofdifferentsmallinhibitormoleculestoanenzyme.Thenecessarystatisticalmechanicaltheoryhadbeenavailableformanyyears

6、.Twonewelementswererequiredtomakethecalculationpossible.Onewastheincreasedpowerofcomputers,whichallowedmoleculardynamicssimulationoftheenzymetrypsininabathofexplicitlyrepresentedwatermolecules.Theotherwastheconceptofusingthermodynamiccyclestorelatethedesiredrelativefreeenergytothatof

7、twononphysicalprocesses:computational"alchemical"transformationsofoneinhibitorintoanotherone,insolutionandinthebindingsite.4Subsequentworkhasshownthatfreeenergycalculationsthatinvolvesystemsaslargeasproteinsorothermacromoleculescanprovideusefullyaccurateresultsinfavorablecases.But,in

8、general,ther