Spherical harmonics coeffcients for ligand-based virtual screening of cyclooxygenase inhibitors

Background: Molecular descriptors are essential for many applications in computational chemistry, such as ligand-based similarity searching. Spherical harmonics have previously been suggested as comprehensive descriptors of molecular structure and properties. We investigate a spherical harmonics descriptor for shape-based virtual screening. Methodology/Principal Findings: We introduce and validate a partially rotation-invariant three-dimensional molecular shape descriptor based on the norm of spherical harmonics expansion coefficients. Using this molecular representation, we parameterize molecular surfaces, i.e., isosurfaces of spatial molecular property distributions. We validate the shape descriptor in a comprehensive retrospective virtual screening experiment. In a prospective study, we virtually screen a large compound library for cyclooxygenase inhibitors, using a self-organizing map as a pre-filter and the shape descriptor for candidate prioritization. Conclusions/Significance: 12 compounds were tested in vitro for direct enzyme inhibition and in a whole blood assay. Active compounds containing a triazole scaffold were identified as direct cyclooxygenase-1 inhibitors. This outcome corroborates the usefulness of spherical harmonics for representation of molecular shape in virtual screening of large compound collections. The combination of pharmacophore and shape-based filtering of screening candidates proved to be a straightforward approach to finding novel bioactive chemotypes with minimal experimental effort

Analysis of Biological Screening Data and Molecular Selectivity Profiles Using Fingerprints and Mapping Algorithms

The identification of promising drug candidates is a major milestone in the early stages of drug discovery and design. Among the properties that have to be optimized before a drug candidate is admitted to clinical testing, potency and target selectivity are of great interest and can be addressed very early. Unfortunately, optimization–relevant knowledge is often limited, and the analysis of noisy and heterogeneous biological screening data with standard methods like QSAR is hardly feasible. Furthermore, the identification of compounds displaying different selectivity patterns against related targets is a prerequisite for chemical genetics and genomics applications, allowing to specifically interfere with functions of individual members of protein families. In this thesis it is shown that computational methods based on molecular similarity are suitable tools for the analysis of compound potency and target selectivity. Originally developed to facilitate the efficient discovery of active compounds by means of virtual screening of compound libraries, these ligand–based approaches assume that similar molecules are likely to exhibit similar properties and biological activities based on the similarity property principle. Given their holistic approach to molecular similarity analysis, ligand–based virtual screening methods can be applied when little or no structure– activity information is available and do not require the knowledge of the target structure. The methods under investigation cover a wide methodological spectrum and only rely on properties derived from one– and two–dimensional molecular representations, which renders them particularly useful for handling large compound libraries. Using biological screening data, these virtual screening methods are shown to be able to extrapolate from experimental data and preferentially detect potent compounds. Subsequently, extensive benchmark calculations prove that existing 2D molecular fingerprints and dynamic mapping algorithms are suitable tools for the distinction between compounds with differential selectivity profiles. Finally, an advanced dynamic mapping algorithm is introduced that is able to generate target–selective chemical reference spaces by adaptively identifying most–discriminative molecular properties from a set of active compounds. These reference spaces are shown to be of great value for the generation of predictive target–selectivity models by screening a biologically annotated compound library. </p

A survey of chemical information systems

A survey of the features, functions, and characteristics of a fairly wide variety of chemical information storage and retrieval systems currently in operation is given. The types of systems (together with an identification of the specific systems) addressed within this survey are as follows: patents and bibliographies (Derwent's Patent System; IFI Comprehensive Database; PULSAR); pharmacology and toxicology (Chemfile; PAGODE; CBF; HEEDA; NAPRALERT; MAACS); the chemical information system (CAS Chemical Registry System; SANSS; MSSS; CSEARCH; GINA; NMRLIT; CRYST; XTAL; PDSM; CAISF; RTECS Search System; AQUATOX; WDROP; OHMTADS; MLAB; Chemlab); spectra (OCETH; ASTM); crystals (CRYSRC); and physical properties (DETHERM). Summary characteristics and current trends in chemical information systems development are also examined

Spherical Harmonics Coefficients for Ligand-Based Virtual Screening of Cyclooxygenase Inhibitors

Molecular descriptors are essential for many applications in computational chemistry, such as ligand-based similarity searching. Spherical harmonics have previously been suggested as comprehensive descriptors of molecular structure and properties. We investigate a spherical harmonics descriptor for shape-based virtual screening.We introduce and validate a partially rotation-invariant three-dimensional molecular shape descriptor based on the norm of spherical harmonics expansion coefficients. Using this molecular representation, we parameterize molecular surfaces, i.e., isosurfaces of spatial molecular property distributions. We validate the shape descriptor in a comprehensive retrospective virtual screening experiment. In a prospective study, we virtually screen a large compound library for cyclooxygenase inhibitors, using a self-organizing map as a pre-filter and the shape descriptor for candidate prioritization.12 compounds were tested in vitro for direct enzyme inhibition and in a whole blood assay. Active compounds containing a triazole scaffold were identified as direct cyclooxygenase-1 inhibitors. This outcome corroborates the usefulness of spherical harmonics for representation of molecular shape in virtual screening of large compound collections. The combination of pharmacophore and shape-based filtering of screening candidates proved to be a straightforward approach to finding novel bioactive chemotypes with minimal experimental effort

Data retrieval in mass spectrometry by an optical coincidence system

The object of this work was to develop an information storage and retrieval system for use in mass spectroscopy. The information to be stored was the compound\u27s name, the mass spectrum, and distinctive physical and chemical properties. It was desirable that the system be one that could be used in the mass spectral laboratory. At the time this project was initiated, no system for mass spectroscopy had been developed with the characteristics of simplicity, rapid retrieval, and practicality of use in the laboratory without elaborate and space consuming equipment. Thus, a system was needed to aid the laboratory personnel in compound identification and prediction of empirical formula and structure