?url_ver=Z39.88-2004&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Adc&rft.relation=http%3A%2F%2Fd-scholarship-dev.library.pitt.edu%2F25568%2F&rft.title=PROBABILISTIC+LATENT+FACTOR+MODELS+FOR+TRANSFORMATIVE+DRUG+DISCOVERY&rft.creator=Cobanoglu%2C+Murat+Can&rft.description=The+cost+of+discovering+a+new+drug+has+doubled+every+9+years+since+the+1950s.+This+can+change+by+using+machine+learning+to+guide+experimentation.+The+idea+I+have+developed+over+the+course+of+my+PhD+is+that+using+latent+factor+modeling+(LFM)+of+the+drug-target+interaction+network%2C+we+can+guide+drug+repurposable+efforts+to+achieve+transformative+improvements.+By+better+characterizing+the+drug-target+interaction+network%2C+it+is+possible+to+use+currently+approved+drugs+to+achieve+therapies+for+diseases+that+currently+are+not+optimally+treated.+These+drugs+might+be+directly+used+through+repurposing%2C+or+they+can+serve+as+a+starting+point+for+new+drug+discovery+efforts+where+they+are+optimized+through+medicinal+chemistry+methods.+To+achieve+this+goal%2C+I+have+developed+LFM-based+techniques+applicable+to+existing+databases+of+drug-target+interaction+networks.+Specifically%2C+I+have+started+out+by+establishing+that+probabilistic+matrix+factorization+(PMF%3B+one+type+of+LFM+algorithm)+can+be+used+as+descriptors+by+showing+they+capture+therapeutic+function+similarities+that+state-of-the-art+3D+chemical+similarity+methods+could+not+capture.+Then+I+have+shown+that+PMF+can+effectively+predict+unknown+drug-target+interactions.+Furthermore%2C+I+have+used+newly+developed+computational+techniques+for+discovering+repurposable+drugs+for+two+diseases%2C+%CE%B11+antitrypsin+(%EF%81%A11-AT)+deficiency+(ATD)+and+Huntington%E2%80%99s+disease+(HD)+leading+to+successful+discoveries+in+both.+For+ATD%2C+two+sets+of+data+generated+by+the+David+Perlmutter+and+Gary+Silverman+laboratories+have+been+used+as+input+to+deduce+potential+targets+and+repurposable+drugs%3A+(i)+a+high+throughput+screening+data+from+a+genome-wide+RNAi+knockdown+in+a+C.+elegans+model+for+studying+ATZ+(Z-allele+of+%EF%81%A11-AT)%2C+and+(ii)+data+from+Prestwick+library+screen+for+the+same+model.+We+have+predicted+that+the+antidiabetic+drug+glibenclamide+would+be+beneficial+against+ATZ+aggregation%2C+and+data+collected+to+date+in+Mus+musculus+models+are+promising.+We+have+worked+on+HD+with+the+Robert+Friedlander+lab%2C+by+examining+the+potential+drugs+and+implicated+pathways+for+15+neuroprotective+(repurposable)+drugs+that+they+have+identified+in+a+two-stage+screening+study.+Based+on+LFM-based+analysis+of+the+targets+of+these+drugs%2C+we+have+developed+a+number+of+hypotheses+to+be+tested.+Among+them%2C+the+antihypertensive+drug+sodium+nitroprusside+appears+to+be+effective+against+HD+based+on+neuronal+cell+death+inhibition+experiments+that+were+conducted+at+the+University+of+Pittsburgh+Drug+Discovery+Institute+as+well+as+the+Friedlander+lab.+Finally%2C+we+have+built+a+web+server%2C+named+BalestraWeb%2C+for+facilitating+the+use+of+PMF+in+repurposable+drug+identification+by+the+broader+community.+BalestraWeb+enables+users+to+extract+information+on+known+and+potential+targets+(or+drugs)+for+any+approved+drug+(or+target)%2C+simply+by+entering+the+name+of+the+query+drug+(or+target).+I+have+also+laid+out+the+framework+for+developing+an+integrated+resource+for+quantitative+systems+pharmacology%2C+Balestra+toolkit+(BalestraTK)%2C+which+would+take+advantage+of+existing+databases+such+as+STITCH%2C+UniProt%2C+and+PubChem.++Collectively%2C+our+results+provide+firm+evidence+for+the+potential+utility+of+machine+learning+techniques+for+assisting+in+drug+discovery.&rft.date=2015-07-10&rft.type=University+of+Pittsburgh+ETD&rft.type=PeerReviewed&rft.format=application%2Fpdf&rft.language=en&rft.identifier=http%3A%2F%2Fd-scholarship-dev.library.pitt.edu%2F25568%2F1%2FFINAL_v2.pdf&rft.identifier=++Cobanoglu%2C+Murat+Can++(2015)+PROBABILISTIC+LATENT+FACTOR+MODELS+FOR+TRANSFORMATIVE+DRUG+DISCOVERY.++Doctoral+Dissertation%2C+University+of+Pittsburgh.++++(Unpublished)++