| OCR Text |
Show 76 Virtual Panel Screening with Climb: A Novel in Silico Method for Determining Protein Kinase Inhibitor Specificity Jeffrey C Walkar (David Bears*) Department Of Biomedkal Engineering^ University of Utah Proteinkiris«iervediIrnpoiiancrtguliioiiIndn^rlddor^dlu^rprccfidstL rtha*longbeenrecognized Thar, rn uiarbnal cha nge* m piMein UiftstsMerfere wtth normal oell u Ldr funufcn and ohen hsad to oncflgeneak Advances In *i i uau ial and i_orn pLjiaclonal ,ji mI m-ilu.....h [oeapbii ihe unique ir.mcr.uul eharactaistles of Uruie* and develop novel irna ll-molec u le Inhibiidi Thar, bind co 11 ¦ proem's Al P pocker ¦ . ¦ ieni cornpucai rtnal rnechodi in^>lve dc< kn iy iinjl l-nfcolec ule compou ndi N^n cherakol I h writs to a single Undit cii^ec In iedrLh of poienc Inhlhcori far lead opr.lnHHTion In sfco screening of brqe unif»LMid dfitd>as£s lias pr»UEd ^veral leadiihacaretunenil^undei^riln^ ihe I DA approval prr> ceaa. Howeverj many potefii Lorn pourrfi have fa [fed to advance In [he dsveloprnencdl plpdi ne due i& low targa £peciricl[y baily recognlclon of proml^uoui corn pounds will -. ¦ resfiafchera time and money m ihe ii •.'in i pco-ctnar*d I > I....."i-i li I ¦ m mJ m orinhlblcor-iargei mieraccioni In i I- ro facllnaie ^p"d VSeficihcdCion of kJnue Inrilblclon ipecihclcy. ^e have developed proprietary ioir niLIMH'"|[hai vlrcuallyiLreenirnuklfiJecargeiia^alnii jungle irnaU-ntelKufelnhltmor I hirty-two-hruaawere Idem ifled and chelncruccura I information wait downloaded from 1 he PrcMeln Daraba^ websrte (PDft - wwwjcsb. or^pdb^ Ualng SchrckJInger'a pr«pram, che1hirty-twoklr«tefJDt:Hruccur« were piepared by r«annlng necet-Hry cofaccor^ removl ng wacer molecufe ar>d «J rl irg bor>d arcfert ar>d ^eomHrlet. After h>drc^en traai mem. the refined Urudu ret wwe iubmrtt«Jfor Crld calculailon co deli neacdvetft« For Inhlbnor docking Allprepa ratcry and Crd (Hkulalbnswere perfonned on an 1536 LlnuK wotb&tbn using the CH.S-AA ftmie fiekJ Im ple-mentfld I n FirstDlK-wef y ui_O. A proven s-mall-molec ule h nase Inhlbkor. WP"-JOa irW>mqen PharmaceurlcaltJ. wataisn prepared ard refined In a similar manner. WP- JOO wars then virtual Iy sc reened agamic a I11 h irty-twi refined klnases- ualrg the C LIME™ Interface, ftn emplrlcally-baiedt_hemScore function Indicating binding affinity was usedia assign each diking E^enarloaGlK^Sc^re The Gllde^corea were rankedTrom higher to lo^eti. and l hen com pared coan In vrtrc-Wnase panel assay Preliminary data supports che use oF virtual screen irc? methods- for cfetermlnlng kmate Inhlbnor tpecificicy CLIMB"" corrected with in wcro daia by accurately predktlng high binding affinities- for ECFFLCDK-2. and whileappr^pr^telyaE-slgnlng bw binding affinities-to nlne1eenc<her compounds rwt inhibited by MP-ZW Though more trials are neecfed to further valkJace 1 h is- tec h nakxpy. h shows promise for reducing cheiimeand cost Involved In pharmaceutical development |
