Over the years numerous papers have presented the effectiveness of various machine learning methods in analyzing drug discovery biological screening data. The predictive performance of models developed using these methods has traditionally been evaluated by assessing performance of the developed models against a portion of the data randomly selected for holdout. It has been our experience that such assessments, while widely practiced, result in an optimistic assessment. This paper describes the development of a series of ensemble-based decision tree models, shares our experience at various stages in the model development process, and presents the impact of such models when they are applied to vendor offerings and the forecasted compounds are acquired and screened in the relevant assays. We have seen that well developed models can significantly increase the hit-rates observed in HTS campaigns.

The mode of action of many pest or disease control agents involves inhibition of some metalloenzyme that is essential for the survival of the target organism. These inhibitors typically consist of a functional group that is capable of a primary binding interaction with the metal and a scaffold that is capable of secondary interactions with the remainder of the enzyme. To characterize the binding ability of various metal binding groups (BGs), we have performed electronic structure calculations on ligand displacement reactions in a model system related to the metalloenzyme, peptide deformylase:  E-M-R + BG → E-M-BG + R. Here E represents a model coordination environment for the metal M, and R is a reference ligand (e.g., water) that may be displaced by a metal binding group. Since the oxidation state of many of the metals considered allows for multiple spin states, we also studied the influence of spin state on the coordination environment. Qualitative considerations of electronic structure inspired by the calculations provide an understanding of binding energy trends across a variety of ligands for a given metal and across a variety of metals for a given ligand.

Quantum mechanical calculations were performed on novel N-phenyl-triazolone inhibitors of the mitochondrial bc1 complex. Both conformational flexibility and rotational barrier were examined. For all of the triazolones investigated, there is generally a large inter-ring torsion angle. The rotational barrier varies considerably among these analogues. For example, when a 6-methyl group is substituted on the phenyl ring at a position ortho to the triazolone, the calculated barrier is large enough to allow atropisomers to be stable even at room temperature. The calculated results are in agreement with experimental studies.

Imidacloprid is increasingly used worldwide as an insecticide. It is an agonist at nicotinic acetylcholine receptors (nAChRs) and shows selective toxicity for insects over vertebrates. Recent studies using binding assays, molecular biology and electrophysiology suggest that both alpha- and non-alpha-subunits of nAChRs contribute to interactions of these receptors with imidacloprid. Electrostatic interactions of the nitroimine group and bridgehead nitrogen in imidacloprid with particular nAChR amino acid residues are likely to have key roles in determining the selective toxicity of imidacloprid. Chemical calculation of atomic charges of the insecticide molecule and a site-directed mutagenesis study support this hypothesis.

The polycyclic dinitriles are a potent class of insecticides which are non-competitive GABA (γ-aminobutyric a acid) antagonists acting at the convulsant site. Comparison with other classes of GABA convulsant site ligands using molecular modelling has shown significant structural similarities. We have developed a pharmacophore model which unifies this class and some previous classes of GABA convulsants. Key pharmacophore elements are a polarizable functionality separated by a fixed distance from two H-bond accepting elements. This model is based on information from X-ray crystal structures and Sybyl using the Tripos force field. Using this pharmacophore model, numerous structural modifications were explored to enhance understanding of structure-activity relationships at the GABA receptor convulsant site of insects and mammals. A radiolabelled bicyclic dinitrile, [ 3 H]BIDN ([ 3 H]3,3-bis-trifluoromethyl-bicyclo[2,2,1] heptane-2,2-dicarbonitrile), was prepared from this area of chemistry and was used as a probe for the interaction of polycyclic dinitriles at the target site.

Ab initio generalized valence bond calculations using effective core potentials are presented for the ground state of (HgF)/sub 2/ and (HgCl)/sub 2/. Extensive calculations are also reported for HgF and compared with previous literature results for HgCl. In spite of the polar nature of the Hg-X bond in the monomer, which would favor a head-to-tail orientation of the dipoles in the dimer, a moderately strong covalent bond between the mercury atoms dictates a linear structure (X-Hg-Hg-X) for both fluoride and chloride. Comparison with solid-state data suggests that the Hg-X bonds shorten upon entering the gas phase. Stability toward disproportionation is problematical. Simple calculations predict the chloride to be about 0.6 eV more stable than Hg + HgCl/sub 2/, while the disproportionation of Hg/sub 2/F/sub 2/ is predicted to be nearly thermoneutral. Improved calculations shed some doubt on the stability of Hg/sub 2/Cl/sub 2/. An improved virtual orbital calculation has been performed to estimate where spectral evidence for the existence of Hg/sub 2/Cl/sub 2/ in the gas phase might be found. 5 tables. 2 figures.

Chemischer InformationsdienstVolume 11, Issue 14 Physical Inorganic Chemistry ChemInform Abstract: STEREOCHEMICAL RIGIDITY AND ISOMERIZATION IN TETRABORANE(4) AND TETRAFLUOROTETRABORANE(4). A THEORETICAL STUDY D. A. KLEIER, D. A. KLEIERSearch for more papers by this authorJ. BICERANO, J. BICERANOSearch for more papers by this authorW. N. LIPSCOMB, W. N. LIPSCOMBSearch for more papers by this author D. A. KLEIER, D. A. KLEIERSearch for more papers by this authorJ. BICERANO, J. BICERANOSearch for more papers by this authorW. N. LIPSCOMB, W. N. LIPSCOMBSearch for more papers by this author First published: April 8, 1980 https://doi.org/10.1002/chin.198014002AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume11, Issue14April 8, 1980 RelatedInformation

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTFluxional behavior in octahydrooctaborate(2-). A theoretical studyDaniel A. Kleier and William N. LipscombCite this: Inorg. Chem. 1979, 18, 5, 1312–1318Publication Date (Print):May 1, 1979Publication History Published online1 May 2002Published inissue 1 May 1979https://doi.org/10.1021/ic50195a029RIGHTS & PERMISSIONSArticle Views66Altmetric-Citations29LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (926 KB) Get e-Alerts Get e-Alerts

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTLocalized molecular orbitals for carbon dioxide and carbonate(2-) ion. A comparison of localization types and a comment on isoelectronic structuresLeo D. Brown, Daniel A. Kleier, and William N. LipscombCite this: J. Am. Chem. Soc. 1977, 99, 21, 6787–6792Publication Date (Print):October 1, 1977Publication History Published online1 May 2002Published inissue 1 October 1977https://doi.org/10.1021/ja00463a001RIGHTS & PERMISSIONSArticle Views127Altmetric-Citations7LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (612 KB) Get e-Alerts Get e-Alerts

Molecular wavefunctions have been generated by the PRDDO (Partial Retention of Diatomic Differential Overlap) method for the monocyclic aromatic rings containing six π-electrons (C4H 4 −2 , C5H 5 − , C6H6, C7H 7 + , and C8H 8 +2 ) and ten π-electron species (C8H 8 −2 , C9H 9 − , C10H10). The eigenvalue spectra of the canonical molecular orbitals are presented. Localized molecular orbitals (LMO's) generated using the Boys criterion are reported for localizations involving all occupied molecular orbitals (complete localizations) and localizations of the π orbitals only. We find evidence for σ-π separation in the complete localizations for some of these molecules even though the Boys criterion is often biased against such results. We demonstrate for C6H6 and find for the other molecules that the π-orbital localizations are indeterminate (i.e. there are an infinite number of equally satisfactory LMO structures between two limiting extremes). This result may be viewed as a corollary of Hückel's (4n+2) rule for aromaticity.

AbstractRöntgenuntersuchungen zeigen, daß die geometrische Struktur großer Boranmoleküle nahe verwandt mit der kleiner Boranmoleküle ist.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTLocalized orbitals in large boron hydrides. Hexadecaborane and related moleculesDavid A. Dixon, Daniel A. Kleier, Thomas A. Halgren, and William N. LipscombCite this: J. Am. Chem. Soc. 1974, 96, 7, 2293–2295Publication Date (Print):April 1, 1974Publication History Published online1 May 2002Published inissue 1 April 1974https://pubs.acs.org/doi/10.1021/ja00814a073https://doi.org/10.1021/ja00814a073research-articleACS PublicationsRequest reuse permissionsArticle Views66Altmetric-Citations10LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts