Structure-Based Virtual Screening New Methods and Applications in Infectious Diseases

" …wealth and greatness are mere trinkets of frivolous utility. […] It is this deception which rouses and keeps in continual motion the industry of mankind. " Adam Smith List of papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals: Improving structure-based virtual screening by multivariate analysis of scoring data. bias of scoring functions in structure-based virtual screening. Mycobacterium tuberculosis ribose-5-phosphate isomerase has a known fold, but a novel active site. Identification of Plasmodium falciparum spermidine synthase active site binders through structure-based virtual screening. Abbreviations Asn Asparagine 4MCHA 4-methylcyclohexylamine 4PE 4-phospho-D-erythronocarboxylic acid 4PEH 4-phospho-D-erythronohydroxamic acid AChE Acetylcholine esterase ACT Artemisinin-based combination therapy AdoDATO S-adenosyl-1,8-diamino-3-thiooctane AdoMet S-Adenosylmethionine AdoMetDC S-Adenosylmethionine decarboxylase CDK2 Cyclin dependent kinase 2 CMR Calculated molecular refractivity COX2 Cyclooxygenase 2 Cys Cysteine dcAdoMet Decarboxylated S-adenolsylmethionine DHFR Dihydrofolate reductase DMSO Dimethylsulphoxide EC Enzyme Commission number ERα Oestrogen receptor α ESI-MS Electrospray ionisation mass spectrometry E. coli Escherichia coli fXa Factor Xa Glu Glutamic acid HAC Heavy atom count His Histidine HIV Human immunodeficiency virus HTS High throughput screening MASC Multiple active site correction MMP-3 Matrix metalloprotease 3 MTA Methylthioadenosine MTB Mycobacterium tuberculosis mtRpiB Mycobacterium tuberculosis Ribose-5-phosphate isomerase B MW Molecular weight NA Neuraminidase NADPH Nicotinamide adenine dinucleotide phosphate NMR Nuclear magnetic resonance ODC Ornithine decarboxylase OPLS-AA Optimized potential for liquid simulations – all atom PCA Principal component analysis PDB Protein data bank Pf Plasmodium falciparum PLS Partial least-squares projections to latent structures PLS-DA PLS discriminant analysis PMF Potentials of mean force R5P Ribose-5-phosphate RAPID Rational approach to pathogen inhibitor discovery RpiB Ribose-5-phosphate isomerase B SBVS Structure-based virtual screening SpdSyn Spermidine synthase SPL Sybyl programming language STD Saturation transfer difference TB Tuberculosis WHO World Health Organization 11 1 Introduction