Descripción del proyecto
EVEN THOUGH MANY GENOMES OF ORGANISMS THAT CAUSE NEGLECTED DISEASES HAVE ALREADY BEEN SEQUENCED AND PUBLISHED FOR MANY YEARS NOW, THERE IS A LACK OF HIGH-QUALITY DRUG TARGETS AND DRUG LEADS AGAINST THOSE DISEASES, THIS IS LIKELY THE CONSEQUENCE OF NEGLECTED DISEASES BEING NOT PROFITABLE (I,E,, WITH NO MARKET IN THE DEVELOPED COUNTRIES), FORTUNATELY, OVER THE RECENT YEARS, THERE HAVE BEEN INCREASED EFFORTS IN ADDRESSING SUCH DEVASTATING DISEASES, WHICH AFFECT ONE OF EVERY SIX PERSON WORLDWIDE, ONE SUCH EFFORT IS OUR TROPICAL DISEASE INITIATIVE (TDI, HTTP://WWW,TROPICALDISEASES,ORG), WHICH COMBINES COMPUTATIONAL AND EXPERIMENTAL STRUCTURAL BIOLOGY TO CHARACTERIZE NEW TARGETS FOR OPEN SOURCE DRUG DISCOVERY AGAINST TROPICAL NEGLECTED DISEASES, OUR GROUP, WHICH IS A FUNDER AS WELL AS ACTIVE MEMBER OF THE TDI, DEVELOPS METHODS FOR COMPARATIVE DOCKING OF SMALL MOLECULES (DRUGS) IN THE SURFACE OF PROTEIN AND RNA STRUCTURES FROM DIFFERENT ORGANISMS THAT CAUSE NEGLECTED DISEASES, ATOMIC-RESOLUTION STRUCTURES OF PROTEINS AND RNA MOLECULES CAN FACILITATE DRUG DISCOVERY BY PRIORITIZING TARGETS FOR DRUG DISCOVERY, IDENTIFYING BINDING SITES FOR SMALL MOLECULES, SUGGESTING DRUG LEADS, AND OPTIMIZING THESE LEADS, IN THE ABSENCE OF AN EXPERIMENTALLY DETERMINED STRUCTURE, COMPARATIVE MODELING HAS PROVED USEFUL BY PROVIDING ACCURATE 3D MODELS, WHICH CAN THEN BE USED WITHIN A DRUG DISCOVERY PIPELINE, OUR GROUP HAS DEMONSTRATED EXPERTISE IN DEVELOPING AND APPLYING STRUCTURAL BIOINFORMATICS METHODS, IN COMBINATION WITH EXPERIMENTS, TO HELP IN EACH OF THE PREVIOUSLY MENTIONED STAGES OF DRUG DISCOVERY,THE BROAD OBJECTIVE OF THIS PROPOSAL IS TO IDENTIFY AND STRUCTURALLY CHARACTERIZE TARGETS (PROTEIN AND RNA) FOR DRUG DISCOVERY AGAINST NEGLECTED DISEASES, THIS OBJECTIVE WILL BE ACCOMPLISHED BY: AIM 1) FURTHER DEVELOPING THE ANNOLYZE METHODOLOGY; AIM 2) APPLYING ANNOLYZE TO GENOMES OF ORGANISMS THAT CAUSE NEGLECTED DISEASES AS WELL AS THEIR VECTORS OF TRANSMISSION; AIM 3) STRUCTURALLY CHARACTERIZING BY NMR A SET OF SELECTED TARGETS WITH POTENTIAL INTEREST FOR DRUG DISCOVERY; AND AIM 4) IMPLEMENTING A NEW METHOD FOR COMPARATIVE RNA STRUCTURE PREDICTION,AIMS 1 TO 3 ARE A NATURAL EXTENSION OF OUR PREVIOUS PLAN NACIONAL (BIO2007/66670), THE IMMEDIATE OUTCOME OF THIS PROPOSAL WILL BE A LIST OF PROTEIN AND RNA TARGETS AND THEIR INTERACTING COMPOUNDS WITH PROMISING THERAPEUTIC APPLICATIONS IN THE DRUG DISCOVERY AGAINST NEGLECTED DISEASES,