The popular docking programs AutoDock, FlexX, and GOLD were used to predict binding modes of ligands in crystallographic complexes including X-ray water molecules or computationally predicted water molecules. Isoenzymes of two different enzyme systems were used, namely cytochromes P450 (n ) 19) and thymidine kinases (n ) 19) and three different "water" scenarios: i.e., docking (i) into water-free active sites, (ii) into active sites containing crystallographic water molecules, and (iii) into active sites containing water molecules predicted by a novel approach based on the program GRID. Docking accuracies were determined in terms of the root-mean-square deviation (RMSD) accuracy and, newly defined, in terms of the ligand catalytic site prediction (CSP) accuracy. Consideration of both X-ray and predicted water molecules and the subsequent pooling and rescoring of all solutions (generated by all three docking programs) with the SCORE scoring function significantly improved the quality of prediction of the binding modes both in terms of RMSD and CSP accuracy.

Tautomers are often disregarded in computer-aided molecular modeling applications. Little is known about the different tautomeric states of a molecule and they are rarely registered in chemical databases. Tautomeric forms of a molecule differ in shape, functional groups, surface, and hydrogen-bonding pattern. Calculation of physical-chemical properties and molecular descriptors differ from one tautomeric state to the other as it is demonstrated with an example of the log P calculation, similarity index, and the complementarity pattern to the targeted protein. Considering tautomery in ligand-protein interactions therefore has a significant impact on the prediction of the ligand binding using various docking techniques. This article points on hitherto unaddressed issue of tautomerism in computer-aided drug design.

A suite of untargeted methods has been applied for the characterization of aerosol from the Tobacco Heating System 2.2 (THS2.2), a heated tobacco product developed by Philip Morris Products S.A. and commercialized under the brand name IQOS®. A total of 529 chemical constituents, excluding water, glycerin, and nicotine, were present in the mainstream aerosol of THS2.2, generated by following the Health Canada intense smoking regimen, at concentrations ≥ 100 ng/item. The majority were present in the particulate phase (n = 402), representing more than 80% of the total mass determined by untargeted screening; a proportion were present in both particulate and gas-vapor phases (39 compounds). The identities for 80% of all chemical constituents (representing > 96% of the total determined mass) were confirmed by the use of authentic analytical reference materials. Despite the uncertainties that are recognized to be associated with aerosol-based untargeted approaches, the reported data remain indicative that the uncharacterized fraction of TPM generated by THS2.2 has been evaluated to the fullest practicable extent. To the best of our knowledge, this work represents the most comprehensive chemical characterization of a heated tobacco aerosol to date.

We are developing a noninvasive approach for targeting imaging and therapeutic radionuclides to prostate cancer. Our method, Enzyme-Mediated Cancer Imaging and Therapy (EMCIT), aims to use enzyme-dependent, site-specific, in vivo precipitation of a radioactive molecule within the extracellular space of solid tumors. Advanced methods for data mining of the literature, protein databases, and knowledge bases (IT.Omics LSGraph and Ingenuity Systems) identified prostatic acid phosphatase (PAP) as an enzyme overexpressed in prostate cancer and secreted in the extracellular space. Using AutoDock 3.0 software, the prodrug ammonium 2-(2 ¶-phosphoryloxyphenyl)-6-iodo-4-(3H)-quinazolinone (IQ 2-P ) was docked in silico into the X-ray structure of PAP. The data indicate that IQ 2-P docked into the PAP active site with a calculated inhibition constant (K i ) more favorable than that of the PAP inhibitor A-benzylaminobenzylphosphonic acid. When 125 IQ 2-P , the radioiodinated form of the water-soluble prodrug, was incubated with PAP, rapid hydrolysis of the compound was observed as exemplified by formation of the water-insoluble 2-(2 ¶-hydroxyphenyl)-6-[125 I]iodo-4-(3H)-quinazolinone ( 125 IQ 2-OH ). Similarly, the incubation of IQ 2-P with human LNCaP, PC-3, and 22Rv1 prostate tumor cells resulted in the formation of large fluorescent IQ 2-OH crystals. No hydrolysis was seen in the presence of normal human cells. Autoradiography of tumor cells incubated with 125 IQ 2-P showed accumulation of radioactive grains ( 125 IQ 2-OH ) around the cells. We anticipate that the EMCIT approach will enable the active in vivo entrapment of radioimaging and radiotherapeutic compounds within the extracellular spaces of primary prostate tumors and their metastases. [Cancer Res 2007;67(5):2197-205]

Small molecule chemistry is of central importance to a number of R&D companies in diverse areas such as the pharmaceutical, nutraceutical, food flavoring, and cosmeceutical industries. In order to store and manage thousands of chemical compounds in such an environment, we have built a state-of-the-art master chemical database with unique structure identifiers. Here, we present the concept and methodology we used to build the system that we call the Unique Compound Database (UCD). In the UCD, each molecule is registered only once (uniqueness), structures with alternative representations are entered in a uniform way (normalization), and the chemical structure drawings are recognizable to chemists and to a cartridge. In brief, structural molecules are entered as neutral entities which can be associated with a salt. The salts are listed in a dictionary and bound to the molecule with the appropriate stoichiometric coefficient in an entity called “substance”. The substances are associated with batches. Once a molecule is registered, some properties (e.g., ADMET prediction, IUPAC name, chemical properties) are calculated automatically. The UCD has both automated and manual data controls. Moreover, the UCD concept enables the management of user errors in the structure entry by reassigning or archiving the batches. It also allows updating of the records to include newly discovered properties of individual structures. As our research spans a wide variety of scientific fields, the database enables registration of mixtures of compounds, enantiomers, tautomers, and compounds with unknown stereochemistries.