化合物效率与先导物优化

ActaPharmaceuticaSinica2013,48(12):1755−17621755*(,100050):,,(metrics),−,:;;;:R916:A:0513-4870(2013)12-1755-08LigandefficiencyandleadoptimizationGUOZong-ru*(InstituteofMateriaMedica,ChineseAcademyofMedicalSciencesandPekingUnionMedicalCollege,Beijing100050,China)Abstract:Pharmacologicalactivityanddruggabilityaretwopivotalfactorsindruginnovation,whicharerespectivelydeterminedbythemicroscopicstructureandmacroscopicpropertyofamolecule.Sincestructuraloptimizationconsistsinamolecularoperationinthespacewithmulti-dimensions,andthereexistsabodyofuncertaintiesfortransductionfrominvitroactivityintoinvivopharmacologicalresponse.Itisnecessaryforearlystageinleadoptimizationtoevaluatecompoundqualityorefficiencyusingakindofmetricscontainingmulti-parameters.Onthebasisofthedescribingparametersofactivityanddruggability,thisoverviewdealswiththerolesofthermodynamicsignaturesandbindingkineticsofdrug-receptorinteractionsinoptimizingqualityofcompounds,signifyingthesignificanceinoptimizationofmicroscopicstructuresfordrugdiscovery.Keywords:ligandefficiency;druggability;microscopoicstructure;slow-offsetdrug,,,,(strangeattractor),,[1],—,,:2013-07-18;:2013-09-08.*Tel/Fax:[phone],E-mail:[e-mail],,,;,(),[2],,;[3],DOI:10.16438/j.0513-4870.2013.12.0111756ActaPharmaceuticaSinica2013,48(12):1755−1762,,,,1,,(),,,[4],,,,,,,,,,,(PC)(PK),,(PD)PCPK,,(),(+)(metrics),,2,,(SAR),,,,2.1:(ligandefficiency,LE),Hopkins[5]KdIC501(ΔG)ΔG=2.303RTlogKd(1)LEΔG(N),,2:LE=−ΔG/N(2)25,LE3:LE=1.36pKd/N(3)3LEkcal·mol−1,kJ·mol−1,ΔG1.36kcal·mol−1,10,[6],,,,,,,30(=405,13.5),Kd=10nmol·L−1,LE=0.37kcal·mol−1Kd=2nmol·L−1,41(=553),4,LE0.29kcal·mol−12.2,LE,LEReynolds[7]800020,,(),LE,LEmax,LEmax,[8]4[9]SILE=−ΔG/(N)0.3(4),(FQ),5[10],FQ=LE/[0.0715+(7.5328/HA)+(25.7079/HA2)−(361.4722/HA3)](5),,(FBDD),,,123,,LEFQ3(AT-9283)[11]2.3:(ligandlipophilicityefficiency,LLE),,:1757LLE:LLE=pIC50–ClogP(6),pIC50IC50(EC50),LogP(),,,,,LLE[12,13],(PR),45(hit-to-lead),LLE,,5(PF-2367982)LLE4,,logPlogD1,−1.36kcal·mol−1,10,,,,,LLElogP23,pIC508,,,LLE6[12,14]PerodaClogPLLE,,ClogP,2.00()LLE,LLE1.53,,,,,[15]2.4LLE,,(LELP)LELP(7)LELPLELLE,[16]LELP=logP/LE(7)3,,KdIC50,,−ΔGKdIC50,ΔG,(ΔH)(−TΔS)ΔG,,,11758ActaPharmaceuticaSinica2013,48(12):1755−17621(ΔH)()()()()()(−TΔS)()()−,()(),ΣΔHΣ(−TΔS)(),,,;3.1HIV(6)(7)HIV,[17],,,5.51;11,−[8](1),Asp30’Asp29’()[18],,1HIVHIVKNI-10033(8),8Kd=13pmol·L−1,ΔH−8.2kcal·mol−1,−TΔS−6.7kcal·mol−1KNI-10033,KNI-10075(9),Asp30B(2),ΔH3.9kcal·mol−1,,,Kd=20pmol·L−1:175928HIV(a);9,Asp30B(b)[19],93.2:,10,,,10X-,S3,,,S3,11150,ITC,11,S3Glu217,Lys224,,10m-p-12,40,9kJ·mol−1,,−,12,13,,[20]44.1,1760ActaPharmaceuticaSinica2013,48(12):1755−1762,,,KdKiIC50,,,,KdKiIC50,,KdIC50,,[21]4.2(),DRDRkonDRkoff8:(8)koffkonKd(),,Kdkoffkon,[22,23],,,(residencetimes,RT)(t1/2(DR)),RTkoff,9[24]:RT=1/kofft1/2(DR)=ln2/koff=0.693/koff(9)RTt1/2(DR),,Kd,,4.3,,Kd,,,24(14,saxagliptin)t1/2(DR)=5.1h[25],(15,vildagliptin)(t1/2(DR)=3.5min)[26],,,(temporaltargetselectivity),,(off-target),[21](16,tiotropiumbromide),M334h,M210,M2,24h[27]MAPKp38,,p38,17(CE-159167)MAPKp38,Ki=3nmol·L−1,ATP,(DFG-in),18(doramapimod),II[28],p38Ki=1nmol·L−1,(DFG-out),,,t1/2(DR)=23h171819,,10(Ki=0.1nmol·L−1),,t1/2(DR)=20h5,,(),,,,,,;:1761,,References[1]HannMM.Molecularobesity,potencyandotheraddictionsindrugdiscovery[J].MedChemComm,2011,2:349−355.[2]GuoZR.Strategyofmoleculardrugdesign:activityanddruggability[J].ActaPharmSin(),2010,45:539−547.[3]GuoZR.Strategyofmoleculardesignofdrugs:theunificationofmacro-propertiesandmicro-structuresofamolecule[J].ActaPharmSin(),2008,43:227−233.[4]GuoZR.Toxicityrisksanddrugdesign[J].ProgPharmSci(),2012,36:1−13.[5]HopkinsAL,GroomCR,AlexA.Ligandefficiency:ausefulmetricforleadselection[J].DrugDiscovToday,2004,9:430−431.[6]Abad-ZapateroC,PerišićO,WassJL,etal.Ligandefficiencyindicesforaneffectivemappingofchemico-biologicalspace:theconceptofanatlas-likerepresentation[J].DrugDiscovToday,2010,15:804−811.[7]ReynoldsCH,BembenekSD,ToungeBA.Theroleofmolecularsizeinligandefficiency[J].BioorgMedChemLett,2007,17:4258−4261.[8]ReynoldsCH,HollowayMK.Thermodynamicsofligandbindingandefficiency[J].ACSMedChemLett,2011,2:433−437.[9]NissinkJWM.Simplesize-independentmeasureofligandefficiency[J].JChemInfModel,2009,49:1617−1622.[10]ReynoldsCH,ToungeBA,BembenekSD.Ligandbindingefficiency:trends,physicalbasis,andimplications[J].JMedChem,2008,51:2432−2438.[11]HowardS,BerdiniV,BoulstridgeJA,etal.Fragment-baseddiscoveryofthepyrazol-4-ylurea(AT9283),amultitargetedkinaseinhibitorwithpotentaurorakinaseactivity[J].JMedChem,2009,52:379−388.[12]RyckmansT,EdwardsMP,HorneVA,etal.RapidassessmentofanovelseriesofselectiveCB2agonistsusingparallelsynthesisprotocols:alipophilicefficiency(LipE)analysis[J].BioorgMedChemLett,2009,19:4406−4409.[13]LeesonP,SpringthorpeB.Theinfluenceofdrug-likeconceptsondecision-makinginmedicinalchemistry[J].NatRevDrugDiscov,2007,6:881−890.[14]EdwardsMP,PriceDA.Roleofphysicochemicalpropertiesandligandlipophilicityefficiencyinaddressingdrugsafetyrisks[J].AnnuRepMedChem,2010,45:381−391.[15]PerodaE.Ananalysisofthebindingefficien