This paper reviews applications of mass spectrometry (MS) to forensic chemistry. Forensic chemistries have to cover the wide range of substances, and a court requests more sensitive and more reliable proof without limit. Thus MS is one of the most dependable technology for forensic chemistry. One of the most important field of forensic chemistry is analysis of drugs and toxicological substances. Especially, analysis of no-information samples so called general unknown screening (GUS) or systematic toxicological analysis (STA) is a challenging task for forensic chemists. The first topic is GUS of biological samples such as whole blood, plasma, urine, and stomach contents using MS. Gas-chromatography (GC)-MS occupied a position of “golden standard” of GUS for a long time. There is no doubt that LC-MS is currently competing with GC-MS to forensic chemistry. Though, developments of GUS procedure by LC-MS have just reported recently. Developments of GUS procedure by LC-MS are discussed about following points of view: interface types (electrospray ionization, ESI and atmospheric pressure chemical ionization, APCI); mass spectrometer (single quadrupole-MS, triplequadrupole-MS, tandem-MS, ion trap-MS, and time-of-flight-MS); mass spectral libraries; and chromatographic systems. Of course sample preparation or extraction is also essential for development of GUS, it lies outside of the scope of this review. Other forensic toxicological applications are discussed about following topics: GC-negative ion chemical ionization (NICI)-MS of benzodiazepines; LC-MS of gamma-hydroxybutyric acid (GHB); LC-inductively coupled plasma (ICP)-MS of phosphorus-containing amino acid type herbicides; LC-MS of quaternary ammonium herbicides; enanthioselective analysis of methamphetamine and related compounds by capillary-electrophoresis (CE)-MS; and single-dose detection of hypnotic sedatives. The other main field of forensic chemistry, analysis of industrial product, is also discussed as follows: ICP-MS of glass fragments, metal fragments of bullet, and dyes; LC-ICP-MS and ion chromatography-ICP-MS of arsenic compounds; pyrolysis-GC-MS of rubber and plastics; and explosive analysis by supercritical fluid chromatography-MS, GC-MS, and LC-MS. As mentioned above, application of MS to many scientific fields and development of analytical science helped forensic chemistry. Applications of MS for forensic chemistry, particularly GUS by LC-MS, might made contributions to other field such as environmental, pharmaceutical, and industrial chemistry.

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Fibrillar aggregates observed in vivo and in vitro are part of “abnormal” structures of proteins. Since many proteins are capable of forming such fibrillar aggregates that share characteristics of the cross-β structure at an atomic level, we consider the fibril structure as one of general states of proteins. It is thus profoundly important to reveal the fibril structure and mechanism of its formation. To this end, mass spectrometry is used as an essential tool by making full use of the inherent sensitivity and high information content. Especially, combination of proteolysis and mass spectrometry is a powerful technique to characterize structural features of the aggregated state of proteins. By identifying fragments produced in the course of proteolysis, it is possible to discern differences in local stability within the analyzed protein and to reconstruct the structure of the mature fibril. In this review, we explain several useful methods to characterize fibrillar aggregates by the combined use of proteolysis and mass spectrometry.

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The progress in genome sequencing projects of a large number of organisms and the advance in mass spectrometry of protein analysis have been significant driving forces in the formation of the field proteomics. The advance in protein mass spectrometry includes development of computer algorithms that use mass spectrometric data to identify proteins in sequence databases. The computer algorithms for protein identification by correlation with sequence databases rely on the availability of constraining parameters that distinguish specific matches from all the other sequences in the database. They can be categorized into three strategies. One of strategies is called “peptide mass fingerprinting,” which is based upon correlating measured masses of peptides derived from digestion of proteins by a residue-specific protease with theoretically calculated peptide masses derived from proteins registered in sequence database. Two strategies for protein identification using tandem mass spectrometry (MS/MS) data are distinguished by demand for interpretation of product ion mass spectra. Product ion mass fingerprinting using uninterpreted MS/MS data of peptides is conceptually similar approach to peptide mass fingerprinting. SEQEUST^® and MS/MS Ions Search in MASCOT^® are the most widely used algorithms for protein identification by searching sequence database using uninterpreted product ion mass spectra. Another strategy using MS/MS data employs the search algorithm by using parameters, such as “peptide sequence tag,” found by manual inspection of product ion mass spectra.

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The decipherment of the human gene has been completed and the analysis of comprehensive structure and mechanism of proteins are currently being performed in the U.S., Europe and Japan. Pharmaceutical companies are utilizing gene and protein information for determining the concept of the new projects and for inventing new compounds. One such an approach is the Structure-Based Drug Design, SBDD. It is drug design process in which the three dimensional structural information of a protein is used directly. Recently, due to the progress in structural analysis, the number of structures being solved is increasing rapidly. Even when the structure of the target-protein is unknown, it is possible to produce a model structure based on the crystal structure of the homologous protein. Many software have been developed for this purpose and some of them can be used on the internet. In this paper, we will introduce the methodology of molecular modeling and docking simulation briefly, and describe some points that should be taken into account when performing simulations. In addition, we will describe the application to drug design using an acetylcholinesterase, AChE, inhibitor as an example. This paper is based on the lecture presented at the BMS conference in last year.

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Pharmacokenetic (PK) properties have been recognized as one of the most important attrition factors in the drug development. Recently, there has been a substantial increase in the variety and number of newly synthesized compounds in the drug discovery stage. Therefore, an improved capacity to evaluate such huge numbers of compounds is one of the most important needs for high-throughput screening. One key to successful analysis technology for PK studies is the LC/MS. However, there is a problem to establishing high-throughput LC/MS. It is important that a suitable LC system is selected from various instruments to analyze with accuracy. For example, short columns, parallel LC systems, unique types of columns, and high flow assays have been examined to find the most rapid and efficient analysis systems. Impurities from reaction mixture or medium should be separated from analytes to get stable detection, as those can alter the ion effect of analytes. In addition to developing these methods, keeping the LC/MS system a good working order is also important, as high-throughput LC/MS is used for continuous screening. High-throughput LC/MS will be indispensable technology to PK studies in drug discovery, but much work has to be done in order to determine which optimal condition will be developed.

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Desorption/ionization on porous silicon (DIOS) is a novel matrix-free variant of laser desorption/ionization (LDI) techniques for mass spectrometry. The DIOS chips are produced by electrochemical etching of silicon wafers under light exposure. In the present report, the optimal conditions, regarding resistivity of silicon wafer, etching current density and etching time, for making DIOS chip with better ionization performance are described. In addition, the DIOS mass spectra of various synthetic polymers including polyethyleneglycol, nonylphenolpolyethoxylate, nonylphenolpolyethoxylatesulfate, polymethylmethacrylate are compared with the matrix-assisted LDI mass spectra.

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A direct gas introduction type atmospheric pressure Penning ionization source for on-site analysis of environmental organic pollutants was developed. The long-lived metastable argon atoms Ar^* (³P₂ and ³P₀) were utilized for Penning ionization. As the excitation energies of Ar^* are 11.5 eV (³P₂) and 11.8 eV (³P₀), the major components of air such as N₂, O₂, CO₂, CO, and H₂O are not ionized with Ar^* but most of the organic compounds can be ionized. Atmospheric pressure Penning ionization mass spectra of all samples studied in our experiment showed abundant molecular-related ions (M⁺, [M+H]⁺, and [M-H]⁺) as base peaks. In the mass spectra of sample gases (M) mixed with methanol, intense ion [M+CH₃]⁺ was observed in addition to [M+H]⁺ and [2M+H]⁺. The appearance of [M+CH₃]⁺ is due to the occurrence of the methyl cation transfer reaction, CH₃OH₂⁺+M→CH₃⁺M+H₂O.

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Chiral recognition of carboxylic acids has been achieved using a “host-metal-guest complexation system” by the ESIMS/EL-guest method. The system consists of a nitrogen-containing acyclic host, La(NO₃)₃, and carboxylic acids. Chiral recognition in the system is evaluated by the IRIS value, which is defined by the relative peak intensities of the corresponding host-metal-guest complex ions:
IRIS = I [(H-La⁺³-G_R^-1(G_ref^-1))⁺¹] / I [(H-La⁺³-G_S-dn^-1(G_ref^-1))⁺¹]
The IRIS values vary from 0.62 to 1.61 and a quantitative cross chiral relationship satisfactorily holds.

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