SHOTGUN DRUG REPURPOSING ALL KNOWN DRUGS FRAGMENT BASED

SHOTGUN DRUG REPURPOSING ALL KNOWN DRUGS FRAGMENT BASED (~5, 000 FROM FDA) DOCKING WITH DYNAMICS (~50, 000) PRIORITISED HITS DISSOCIATION CONSTANTS (KD) (~300 -500) + ALL TARGETS WITH KNOWN STRUCTURE (~5, 000 -10, 000) MACHINE LEARNING IN VITRO STUDIES herpes, malaria, dengue hepatitis C, dental caries HIV, HBRV, XMRV, rabies, encephalitis, cholera, tuberculosis, various cancers M Lagunoff (UW), W Van Voorhis (UW), S Michael (FCGU), J Mittler/J Mullins (UW), G Wong/A Mason/L Tyrell (U Alberta), W Chantratita/P Palittapongarnpim (Thailand) CLINICAL STUDIES/APPLICATION INITIAL CLINICAL TRIALS IN VIVO STUDIES

PROSPECTIVE PRELIMINARY VERIFICATION Predicted protease (dimer) + inhibitor: DENGUE HERPES (HSV, CMV, KSHV) Viral E protein Observed: Function is inactivated. Prediction #1 Prediction #2 KD protease ligand ≤ μM KD protease dimer ≤ μM Herpes viral load Experiment 1 Experiment 2 2/4 ≤ µM ED 50 against dengue virus PLo. S Neglected Tropical Diseases, 2010. 14 targets MALARIA Multitarget protocol: 2, 344 → 16 → 6 ≤ 1 µM ED 50 HTS protocol: 2, 687 → 19 ≤ 1 µM ED 50 HTS protocol: 2, 160 → 36 ≤ 1 µM ED 50 Docking protocol: 355, 000 → 1 ≤ 10 µM ED 50 Docking protocol: 241, 000 → 84 → 4 ≤ 10 µM ED 50 Trends in Pharmacological Sciences, 2010. Lagunoff/ Van Voorhis/ Michael