Bioinformatics, computational chemistry and structural biology: Development and application of methods to drug design and discovery.

摘要

Bioinformatics, computational chemistry and structural biology tools play a critical role in the traditional drug discovery and the gene-based drug discovery. In this informatics era, the knowledge of genomics coupled with immense computational power, can lead to better understanding of mechanisms of disease and drug action and improved therapeutics based on structure based drug design and gene therapy. This dissertation deals with the development and application of these tools to drug design and problems of therapeutic interest.; In Chapter 1, genomics combined with pathophysiological information, were used to predict novel genes in hemorrhagic fever viruses like Ebola. A new method for predicting novel selenoprotein genes was developed and applied to the genomics studies of these hemorrhagic fever viruses.; Chapter II emphasizes the fact that structure is more conserved than the sequence during the evolutionary process. Structural evaluation of distant homology method combines the structural, genomic, and experimental information and it can be used to study distantly related proteins. In our study, this method is used to evaluate a predicted relationship between two classes of enzymes, exonucleases and RNases, in the light of experimental results (X-ray).; Chapter III deals with the application of computational chemistry and bioinformatics to study the relationship between a peptide and class of biologically important small molecules, ergot alkaloids. An inverse folding algorithm was used in the initial structural prediction. Molecular dynamics simulation was used to optimize the structure and also in conformational sampling of the peptide. Systematic search method was then applied to the optimized peptide to study the possible structural relationship with the ergot alkaloids.; The first chapter in the appendix deals with the prediction of novel genes in human immunodeficiency virus (HIV-1). The appendix also includes the abstracts of other projects: (2) Homology modeling and molecular dynamics simulation studies of a hypothetical HIV-1 DNA binding protein, (3) COMFA studies of HIV-1 integrase inhibitors, (4) Signal transduction in G-protein coupled receptors, (5) Structural model of HIV-1 integrase, (6) Antiviral drug resistance mutations in human immunodeficiency virus type I reverse transcriptase occur in specific RNA structural regions and (7) Molecular modeling of promethazine and trimipramine enantiomers on selected HPLC chiral stationary phases.