Size estimation of chemical space: how big is it?

Objectives To estimate the size of organic chemical space and its sub‐regions, i.e. drug‐like chemical space and known drug space (KDS). Methods Analysis of the growth of organic compounds as a function of their carbon atoms based on a power function (f(x) = A×B, C = x) and an exponential function (f(x) = AeBx). Also, the statistical distribution of KDS and drug‐like chemical space (drugs with good oral‐bioavailability) based on their carbon atom count was used to deduce their size. Key findings The power function (f(x) = A×B, C = x) gives a superior fit to the growth of organic compounds leading to an estimate of 3.4 × 109 populating chemical space. KDS is predicted to be 2.0 × 106 molecules and drug‐like chemical space is calculated to be 1.1 × 106 compounds. Conclusions The values here are much smaller than previously reported. However, the numbers are large but not astronomical. A clear rationale on how we reach these numbers is given, which hopefully will lead to more refined predictions.     

Pulmonologist evaluation on new CT visualization for guidance to lung lesions during bronchoscopy

Objective: Endoluminal visualization in virtual and video bronchoscopy lacks information about the surrounding structures, and the traditional 2?D axial, coronal and sagittal CT views can be difficult to interpret. To address this challenge, we previously introduced a novel visualization technique, Anchored to Centerline Curved Surface, for navigated bronchoscopy. The current study compares the ACCuSurf to the standard ACS CT views as planning and guiding tools in a phantom study.

Material and methods: Bronchoscope operators navigated in physical phantom guided by virtual realistic image data constructed by fusion of CT dataset of phantom and anonymized patient CT data. We marked four different target positions within the virtual image data and gave 12 pulmonologists the task to navigate, with either ACCuSurf or ACS as guidance, to the corresponding targets in the physical phantom.

Results: Using ACCuSurf reduced the planning time and increased the grade of successful navigation significantly compared to ACS.

Conclusion: The phantom setup with virtual patient image data proved realistic according to the pulmonologists. ACCuSurf proved superior to ACS regarding planning time and navigation success grading. Improvements on visualisation or display techniques may consequently improve both planning and navigated bronchoscopy and thus contribute to more precise lung diagnostics.     

A new visualization method for navigated bronchoscopy

Objective: In flexible endoscopy techniques, such as bronchoscopy, there is often a challenge visualizing the path from start to target based on preoperative data and accessing these during the procedure. An example of this is visualizing only the inside of central airways in bronchoscopy. Virtual bronchoscopy (VB) does not meet the pulmonologist’s need to detect, define and sample the frequent targets outside the bronchial wall. Our aim was to develop and study a new visualization technique for navigated bronchoscopy.

Material and methods: We extracted the shortest possible path from the top of the trachea to the target along the airway centerline and a corresponding auxiliary route in the opposite lung. A surface structure between the centerlines was developed and displayed. The new technique was tested on non-selective CT data from eight patients using artificial lung targets.

Results: The new display technique anchored to centerline curved surface (ACCuSurf) made it easy to detect and interpret anatomical features, targets and neighboring anatomy outside the airways, in all eight patients.

Conclusions: ACCuSurf can simplify planning and performing navigated bronchoscopy, meets the challenge of improving orientation and register the direction of the moving endoscope, thus creating an optimal visualization for navigated bronchoscopy.     

Bond stability of the "undesirable" heteroatom-heteroatom molecular moieties for high-throughput screening libraries

Compounds containing heteroatom–heteroatom bonds are regarded as “undesirable” in drug discovery projects possibly due to their inherent fragility, i.e., low bond dissociation energies (BDEs). However, many marketed drugs contain these molecular moieties and it can therefore be argued that the drugs have stronger bonds than generic organic compounds. In this study heteroatom–heteroatom BDEs for marketed drugs and non-drugs are calculated using the Density Functional Theory (DFT). The compounds containing heteroatom–heteroatom moieties were separated into six groups, i.e., N–N, N–O, N–S, O–S, O–O and S–S. No statistical difference was found for the N–N, N–O and O–S groups between the drugs and non-drugs. A statistical significant difference of ∼10 kcal mol⁻¹was observed for the N–S moiety however all of the compounds investigated were sulphonamides. No drugs with the O–O moiety were found and the generic organic compounds had very low average BDE (26.6 ± 4.0 kcal mol⁻¹) explaining their absence. For the S–S scaffold not enough data was available to make a meaningful statistical analysis. The results indicate that low BDE is not the main factor why heteroatom–heteroatom compounds are excluded from drug discovery projects. A more plausible explanation is their electron rich nature which leaves them susceptible to electrophilic attack in biochemical assays, which often leads to false positives and renders this class of compounds “undesirable” in screening collections. However, by omitting these compounds valuable areas in chemical space can be overlooked.     

Mutagenic potential of nitrenium ions of nitrobenzanthrones: correlation between theory and experiment

The mutagenic activity of nine substituted nitrobenzanthrone (NBA) derivatives was recently established in the Ames assay and ranged from near inactivity to extremely high mutagenic activity (Takamura-Enya et al. 2006: Mutagenesis 21:399-404). Using thermochemical and molecular modeling techniques, the activation pathway of these NBA derivatives, namely 1-nitro-, 2-nitro-, 3-nitro-, 9-nitro-, 11-nitro-, 1,9-dinitro-, 3,9-dinitro-, 3,11-dinitro-, and 3,9,11-trinitrobenzanthrone, and the formation of the corresponding aryl-nitrenium ions, were investigated using density functional theory calculations. The calculated properties of the NBA derivatives were systematically compared with their bacterial mutagenic potency. Accommodation of the ligand substrates into the binding pocket of the bacterial nitroreductases was not sterically inhibited for the NBAs. Moreover, electron affinities, water elimination energies, esterification, and solvolysis energies did not reveal any possible links with the observed mutagenic potency of the NBAs. However, a strong negative linear correlation was found when the relative energies of the nitrenium ions of the mono and disubstituted NBAs were plotted against the logarithm of the mutagenic potency of the NBAs found in the different Salmonella typhimurium strains. Therefore, our data clearly indicate that the stability of the nitrenium ions is one critical determinant of the mutagenic potency of NBAs in Salmonella tester strains.     

Mutagenicity and DNA adduct formation by the urban air pollutant 2-nitrobenzanthrone.

2-Nitrobenzanthrone (2-NBA) has recently been detected in ambient air particulate matter. Its isomer 3-nitrobenzanthrone (3-NBA) is a potent mutagen and suspected human carcinogen identified in diesel exhaust. The highest mutagenic activity of 2-NBA tested in Salmonella typhimurium was exhibited in strain TA1538-hSULT1A1 expressing human sulfotransferase (SULT) 1A1. 2-NBA also induced mutations in Chinese hamster lung V79 cells expressing human N-acetyltransferase 2 or SULT1A1, but no mutagenicity was observed in the parental cell line. DNA adduct formation in vitro was examined in different human cell lines by thin-layer chromatography (32)P-postlabeling. Whereas 3-NBA formed characteristic DNA adducts in lung A549, liver HepG2, colon HCT116, and breast MCF-7 cells, 2-NBA-derived DNA adducts were only observed in A549 and HepG2 cells, indicating differences in the bioactivation of each isomer. The pattern of 2-NBA-derived DNA adducts in both cell lines consisted of a cluster of up to five adducts. In HepG2 cells DNA binding by 2-NBA was up to 14-fold lower than by 3-NBA. DNA adduct formation of 2-NBA was also investigated in vivo in Wistar rats treated with a single dose of 2, 10, or 100 mg/kg body weight (bw). No DNA adduct formation was detected at doses of up to 10 mg/kg bw 2-NBA, even though 3-NBA induced DNA adducts at a dose of 2 mg/kg bw. Only after administration of one high dose of 100 mg/kg bw 2-NBA was a low level of DNA adduct formation detected, and then only in lung tissue. Density functional theory calculations for both NBAs revealed that the nitrenium ion of the 3-isomer is considerably more stable ( approximately 10 kcal/mol) than that of the 2-isomer, providing a possible explanation for the large differences in DNA adduct formation and mutagenicity between 2- and 3-NBA.     

Molecular cloning and functional expression of the first two specific insect myosuppressin receptors

The Drosophila Genome Project database contains the sequences of two genes, CG8985 and CG13803, which are predicted to code for G protein-coupled receptors. We cloned the cDNAs corresponding to these genes and found that their gene structures had not been correctly annotated. We subsequently expressed the coding regions of the two corrected receptor genes in Chinese hamster ovary cells and found that each of them coded for a receptor that could be activated by low concentrations of Drosophila myosuppressin (EC50,4 x 10(-8) M). The insect myosuppressins are decapeptides that generally inhibit insect visceral muscles. Other tested Drosophila neuropeptides did not activate the two receptors. In addition to the two Drosophila myosuppressin receptors, we identified a sequence in the genomic database from the malaria mosquito Anopheles gambiae that also very likely codes for a myosuppressin receptor. To our knowledge, this paper is the first report on the molecular identification of specific insect myosuppressin receptors.