Molecular Modeling of Novel Tryptamine Analogs with Antibiotic Potential Through Their Inhibition of Tryptophan Synthase

............................................................................................................................ 3 INTRODUCTION .................................................................................................................. 4 THE ARMS RACE – BACTERIAL EVOLUTION OF ANTIBIOTIC RESISTANCE ................................. 4 ANTIBIOTIC DRUG DISCOVERY – FROM PENICILLIN TO THE “GOLDEN AGE” ............................ 7 THE PUBLIC HEALTH CRISIS ...................................................................................................... 9 THE CURRENT STATE OF ANTIBIOTIC DRUG DEVELOPMENT ................................................... 12 IDENTIFYING TRYPTOPHAN SYNTHASE AS A POTENTIAL ANTIBIOTIC TARGET ........................ 14 TRYPTAMINE ANALOGS AS NOVEL ANTIBIOTICS ..................................................................... 17 MATERIALS AND METHODS ......................................................................................... 20 NOMENCLATURE AND IDENTIFICATION SYSTEM OF THE TRYPTAMINE ANALOGS .................... 20 MOLECULAR MODELING OF THE TRYPTAMINE ANALOGS ........................................................ 21 BINDING AFFINITY ANALYSIS OF TRYPTOPHAN SYNTHASE SUBUNITS-TRYPTAMINE ANALOGS COMPLEXES ............................................................................................................................. 23 BINDING AFFINITY ANALYSIS OF HUMAN MAOB-TRYPTAMINE ANALOGS COMPLEXES ........ 24 MOLECULAR MODELING OF COMPLEXES BETWEEN TRYPTOPHAN SYNTHASE SUBUNITS OR HUMAN MAOB AND IDENTIFIED TRYPTAMINE ANALOGS COMPLEXES .................................. 25 RESULTS .............................................................................................................................. 26 BINDING AFFINITY ANALYSIS OF TRYPTOPHAN SYNTHASE SUBUNITS-TRYPTAMINE ANALOGS COMPLEXES ............................................................................................................................. 26 BINDING AFFINITY ANALYSIS OF HUMAN MAOB-TRYPTAMINE ANALOGS COMPLEXES ........ 31 INTEGRATING THE TRYPTAMINE ANALOGS’ BINDING AFFINITIES TO TRYPTOPHAN SYNTHASE AND MAOB ............................................................................................................................. 33 IDENTIFICATION OF THE TRYPTAMINE ANALOGS DESERVING SYNTHESIS AND FURTHER RESEARCH ............................................................................................................................... 34 DISCUSSION ........................................................................................................................ 42 WORKS CITED ................................................................................................................... 46 APPENDICES ....................................................................................................................... 50 PROVISIONAL PATENT APPLICATION RECEIPT ......................................................................... 50