Computer-based system for correlating molecular structures with mass spectral data

Algorithms are described for correlating a proposed molecular structure with a mass spectrum. All molecular substructures of a proposed structure are determined which have the same masses as the fragment ions. The most likely fragment ion structures are those molecular substructures formed with the fewest number of bond cleavages in the proposed structure. The algorithms, which incorporate methods for handling rearrangement and adduct ions, utilize either nominal or exact data originating from any ionization method. The algorithms are demonstrated using the mass spectra of a substituted azetidinyl ketone and the macrolide antibiotic avermectin A_1a.     

Computer-based system for correlating molecular structures with mass spectral data Methods for generating molecular substructures and for incorporating fragmentation rules

The masses of ions observed in the mass spectrum of a pure compound are correlated with the masses of the molecular substructures of the compound. Three methods are described for generating molecular substructures. Each method is evaluated to establish how effectively it generates the molecular substructures and correlates the masses of the molecular substructures with the masses of the observed fragment ions. Rules for mass-spectral fragmentation processes are incorporated into the mass spectral analysis software and illustrated for retro-aldol and lactone-ester reactions occurring in the thermospray mass spectra of oligomycin antibiotics.     

Computer Assisted Structural Interpretation of Mass Spectral Data

An interactive system of programs has been developed to assist in structure elucidation based on mass spectral data. The program relies on algorithms for generating all the structural isomers that constitute alternative explanations of the observed data and it associates relative plausibility values with the different isomers. The structure assembly part of the program allows for the use of overlapping substructural components, such as substructures inferred from the appearance of particular ion patterns in the spectrum of an unknown compound. Mass spectrum interpretation procedures used with this structure assembly process could exploit any form of spectrum-substructure correlation scheme. In this work, the emphasis has been on the use of detailed and class specific spectrum-substructure correlations. Applications of the program are illustrated by means of an example analysis of the mass spectra of a variety of marine sterols.     

Algorithms for automatic interpretation of high resolution mass spectra

Automated interpretation of high-resolution mass spectra in a reliable and efficient manner represents a highly challenging computational problem. This work aims at developing methods for reducing a high-resolution mass spectrum into its monoisotopic peak list, and automatically assigning observed masses to known fragment ion masses if the protein sequence is available. The methods are compiled into a suite of data reduction algorithms which is called MasSPIKE (Mass Spectrum Interpretation and Kernel Extraction). MasSPIKE includes modules for modeling noise across the spectrum, isotopic cluster identification, charge state determination, separation of overlapping isotopic distributions, picking isotopic peaks, aligning experimental and theoretical isotopic distributions for estimating a monoisotopic peak's location, generating the monoisotopic mass list, and assigning the observed monoisotopic masses to possible protein fragments. The method is tested against a complex top-down spectrum of bovine carbonic anhydrase. Results of each of the individual modules are compared with previously published work.     

Multidimensional computer evaluation of mass spectra

The increasing importance of spectroscopic methods as an analytical tool in industry, combined with the trend to automatize spectrometers, demands new standards in the quantity and quality of spectrum interpretation. Suitable computer programs should be able to predict structural features from mass spectral properties. The knowledge base is a structure-oriented mass spectral data collection consisting of some 42000 spectra and topologies. The comparison of selected mass spectral properties such as similarity, neutral losses and ion series of the unknown with the equivalent properties of the library spectra results in a set of corresponding structures. Subsequent substructure analysis yields a histogram of substructure frequencies containing information about their statistical relevance. The relevant substructure set may be recombined to produce a structure proposal, as is demonstrated for 1-acetyl-2-methoxy-4-trimethylsilyioxybenzene. In a second example, the relevant substructures derived by the interpretation system are used as input for the ¹³C-NMR substructure generator. This procedure reduces the solution space of the structure prediction algorithm considerably. Besides the spectrum interpretation, additional possibilities are available. The substructure search enables us, for example, to look for mass spectrometric reaction centres. Beyond that, substructure analysis is applicable to the determination of structural features typical of certain combinations of neutral losses and/or characteristic fragments.     

MASSIS: a mass spectrum simulation system 1. Principle and method

A mass spectrum simulation system was developed. The simulated spectrum for a given target structure is computed based on the cleavage knowledge and statistical rules established and stocked in pivot databases: cleavage rule knowledge, function groups, small fragments and fragment-intensity relationships. These databases were constructed from correlation charts and statistical analysis of large population of organic mass spectra using data mining techniques. Since 1980, several systems were proposed for mass spectrum simulation, but in present there is no any commercial software available. This shows the complexity and difficulties in the development of a such system. The reported mass spectral simulation system in this paper could be the first general software for organic chemistry use     

Spec2D: a structure elucidation system based on 1H NMR and H-H COSY spectra in organic chemistry

A system for structure elucidation based on proton NMR spectra has been developed. The system, named Spec2D (system for spectra from 2D-NMR), incorporates 1H NMR and H-H correlation spectroscopy (COSY) spectral information obtained from 2D-NMR experiments. 2D-NMR is important for the structure elucidation because it provides information about the relationships among differently situated protons in the structures of unknown compounds. The system uses the concepts of molecular graphs. The improved representation of substructures as well as several novel algorithms for structure generation have been devised to solve the combinatorial problem and to reduce the processing time. Spec2D consists of a knowledge base, an analysis module, and a candidate structure generator module. Spec2D proposes candidate structures from only 1H NMR and H-H COSY spectral information of an unknown compound without any 13C NMR spectral or structural information, such as molecular formulas. Spec2D has the capability to propose the "new" structure of an unknown compound, if the corresponding substructures are included in the knowledge base.     

Direct evidence for preformed ions of porphyrins in the solvent matrix for fast atom bombardment mass spectrometry

The observation that protonated molecules are present in solvents utilized for fast atom bombardment (FAB) mass spectrometric studies has been demonstrated using visible absorption spectrometry. Addition of porphyrins to thioglycerol, a solvent used for FAB analyses, results in partial protonation of the molecule. This reaction can be monitored by observing the shift in visible absorption maxima associated with the molecular transition from free base to protonated structure. A good correlation is observed between the degree of protonation indicated by the appropriate absorption bands and the abundance of the [M + H]⁺ ion in the FAB spectrum of the corresponding solution. Addition of certain non-polar porphyrin molecules to thioglycerol does not result in the protonation of the molecule in solution; in these cases, analyses of the corresponding solutions by FAB do not yield [M + H]⁺ ions. Subsequent addition of trifluoroacetic acid to the solvent has proved sufficient to protonate the analyte molecule, as indicated by the visible absorption spectrum; FAB analyses of these non-polar porphyins in acidified solvent result in the observation of [M + H]⁺ ions. These experiments demonstrate that analyses of these analyte molecules requires that they be present as ions in solution prior to analysis by FAB. This study provides experimental evidence for the presence of ions in solutions employed for FAB analysis, suggesting that these ions are essential for the generation of the protonated molecules observed during FAB mass spectrometric analyses.     

High-throughput, accurate mass liquid chromatography/tandem mass spectrometry on a quadrupole time-of-flight system as a 'first-line' approach for metabolite identification studies

Throughput for drug metabolite identification studies has been increased significantly by the combined use of accurate mass liquid chromatography/tandem mass spectrometry (LC/MS/MS) data on a quadrupole time-of-flight (QTOF) system and targeted data analysis procedures. Employed in concert, these tools have led to the implementation of a semi-automated high-throughput metabolite identification strategy that has been incorporated successfully into lead optimization efforts in drug discovery. The availability of elemental composition data on precursor and all fragment ions in each spectrum has greatly enhanced confidence in ion structure assignments, while computer-based algorithms for defining sites of biotransformation based upon mass shifts of diagnostic fragment ions have facilitated identification of positions of metabolic transformation in drug candidates. Adoption of this technology as the 'first-line' approach for in vitro metabolite profiling has resulted in the analysis of as many as 21 new chemical entities on one day from diverse structural classes and therapeutic programs.     

N-二异丙基磷酰基氨基酸的电子电离和快原子轰击质谱的比较

N-二异丙基磷酰基(DIPP)氨基酸的快原子轰击(FAB)和电子电离(EI)质谱都有相似的丢失两分子丙烯和一分子甲酸的碎裂过程.在FAB中,连续失掉两个丙烯,然后脱去甲酸的过程较为有利;在EI中则主要为先脱去甲酸,随后失去丙烯,本文对DIPP-氨基酸的FAB和EI质谱碎裂历程进行了比较,对分子离子峰的形式与碎裂方式的关系进行了讨论.     

Structure-specific fragmentations of 2,2,4-trisubstituted 1,2-dihydroquinazolines

Fragmentations of a series of 2,2,4-trisubstituted 1,2-dihydroquinazolines were studied by electron impact (EI) ionization and positive- and negative-ion fast atom bombardment (FAB) coupled with collision-induced decomposition (CID). The EI mass spectra give information that directly indicates the specific location of each substituent. The FAB–CID spectra provide data regarding the masses of each substituent, but no definitive information regarding location.     

Conversion of Ca2+ salt of an organic compound to its Li+ salt to simplify the fast atom bombardment mass spectrum

The FAB mass spectrum of the Ca(2+) salt of RK-682 (1, MW 368), a potent protein tyrosine phosphatase inhibitor, shows a complex pattern due to Ca(2+) adduct ions with multimers of 1 and their decomposition ions. Addition of LiCl greatly simplified the FAB mass spectrum, providing a prominent Li(+) adduct ion of 1 at m/z 381 [M+2Li-H](+). The addition of LiCl also greatly simplified the FAB mass spectrum of calcium pantothenate. This approach may be generally useful for molecular weight determination of multivalent metal salts of organic compounds, or organic compounds that can form Li salts, by FAB mass spectrometry.     

Structural study of PLGA [copoly (DL-lactic/glycolic acid)], a biodegradable polymer for parenteral sustained release preparations, by tandem mass spectrometry.

A copoly (DL-lactic/glycolic acid) (PLGA), with a weight-average molecular weight of about 8400, has been characterized using fast atom bombardment (FAB)-tandem mass spectrometry in order to determine the sequence. Because of the large molecular size, PLGA was partially hydrolyzed and the terminal hydroxyl groups in the resulting oligomer mixture acetylated as the indicator. The FAB spectrum of this sample showed a complex ion signal pattern containing monomer to octamer. Diagnostic product ions containing useful information for sequence determination were observed in collision-induced dissociation-MS/MS and MS/MS/MS of these oligomer ions. The results of analysis for dimers through pentamers showed that they have random sequences of lactic and glycolic acid, suggesting that the whole structure of PLGA also has a random sequence.     

IR, MS studies on (+/-)-1-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine dihydrochloride salt

The vibration spectrum and FAB mass spectrum of (+/-)-1-[3-(2-methoxyphenoxy)-2-hydroxypropyl]-4-[(2,6-dimethylphenyl)aminocarbonylmethyl]piperazine dihydrochloride salt was studied. By comparing with the spectra of free base, different bands of IR were found in the NH+ stretching, the NH+ deformation motion, the CH2 of NCH2 group symmetric stretching, the CH2 of N-CH2 group twisting and the CN stretching. FAB shows the basic peak is M + H. Other m/e peaks are consistent with the structure.     

Computer-aided interpretation of mass spectra. Information on substructural probabilities form stirs

The capability of the ‘Self-Training Interpretive and Retrieval System’ has been extended so that the compounds selected as providing the best match in each data class to the unknown mass spectrum are examined by the computer for the presence of each of 179 common substructural fragments. Stastical methods were used to evaluate the selectivity for identification of each substructure by each data class using a reference file of 18 806 spectra of different compounds. In tests using at least 373 unknown spectra for each of the substructures, with criteria that gave a mean reliability of 98.1%, the method averaged 49% recall, which corresponds to the identification of 2.55 substructures per unknown spectrum, as well as the normal “Self-Training Interpretative and Retrieval System” match-factor results, requires 68 s on a laboratory computer. The method is also available to outside users on an international computer network.     

Mass spectrometry of modified nucleic acid bases and nucleosides. 2. Class II mesoionic nucleosides and bases derived from thiazolo[3,2-a]pyrimidine-5,7-diones

The mass spectral characteristics of novel Class II mesoionic heterocyclic bases and nucleosides based on the thiazolo[3,2-a]pyrimidine-5,7-dione system have been examined using low and high resolution mass spectrometry and metastable ion analysis. The mass spectra of these Class II mesoionic nucleosides differ significantly from the spectra of “normal” nucleosides by the absence of fragment ions associated with the base plus portions of the sugar. The difference in fragmentation is rationalized on the basis of exclusive localization of the radical-charge site in the aglycone, a result of the mesoionic structure of these molecules. The fast atom bombardment (FAB) mass spectra of a Class I mesoionic nucleoside, 7-methylguanosine, is compared to the FAB mass spectra of the Class II mesoionic nucleosides.     

Tandem mass spectrometry of aminated fullerene derivatives

The products of the reaction between fullerenes (C₆₀/C₇₀) and dimethylamine were investigated by fast atom bombardment (FAB) mass spectrometry and tandem mass spectrometry (MS/MS). The FAB mass spectrum shows peaks corresponding to the addition of up to eight dimethylamine species, exclusively to C₇₀. MS/MS reveals an unusual fragmentation pattern. The mass spectrum of the reaction products, together with a number of tandem mass spectra, are shown.     

基于稀疏模型的气相色谱-质谱数据解析及其在严重重叠峰解析中的应用

提出一种气相色谱-质谱（GC-MS）数据解析算法。以色谱峰顶点处的质谱作为待测谱,在谱库中检索一定量相关参考谱,求解关于各纯组分色谱响应值的方程。质谱检索采取分步策略,先利用质谱碎片规律建立高速索引进行粗选,然后使用强峰高概率出峰准则和耐挤压性准则排除无关质谱。为求解色谱响应值方程,提出基于稀疏模型的回归算法,相比传统算法,稀疏算法利于提取待测谱的主要结构,避免"过拟合"。实验结果表明,该质谱检索算法具有较高的精度和规模较小的剩余参考谱集,而所提稀疏模型算法可有效解析严重重叠峰。该算法可作为GC-MS重叠峰解析,特别是严重重叠峰解析的一种有效解决方案。