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Papers by Stephan Reiling

Research paper thumbnail of Theoretical investigations on the structure and physical properties of cellulose

Research paper thumbnail of A novel computational method for comparing vibrational circular dichroism spectra

Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 2010

A novel method, SimIR/VCD, for comparing experimental and calculated VCD (vibrational circular di... more A novel method, SimIR/VCD, for comparing experimental and calculated VCD (vibrational circular dichroism) spectra is developed, based on newly defined spectra similarities. With computationally optimized frequency scaling and shifting, a calculated spectrum can be easily identified to match an observed spectrum, which leads to an unbiased molecular chirality assignment. The time-consuming manual band-fitting work is greatly reduced. With (1S)-(-)-alpha-pinene as an example, it demonstrates that the calculated VCD similarity is correlated with VCD spectra matching quality and has enough sensitivity to identify variations in the spectra. The study also compares spectra calculated using different DFT methods and basis sets. Using this method should facilitate the spectra matching, reduce human error and provide a confidence measure in the chiral assignment using VCD spectroscopy.

Research paper thumbnail of Prediction of the 3D Structure and Dynamics of Human DP G-Protein Coupled Receptor Bound to an Agonist and an Antagonist

Journal of the American Chemical Society, 2007

Prostanoids play important physiological roles in the cardiovascular and immune systems and in pa... more Prostanoids play important physiological roles in the cardiovascular and immune systems and in pain sensation in peripheral systems through their interactions with eight G-Protein Coupled Receptors. These receptors are important drug targets, but development of subtype specific agonists and antagonists has been hampered by the lack of 3D structures for these receptors. We report here the 3D structure for the human DP G-Protein Coupled Receptor (GPCR) predicted by the MembStruk computational method. To validate this structure we use the HierDock computational method to predict the binding mode for the endogenous agonist (PGD2) to DP. Based on our structure, we predicted the binding of a new family of antagonists which has been confirmed experimentally.

Research paper thumbnail of Similarity Searching of Chemical Databases Using Atom Environment Descriptors (MOLPRINT 2D): Evaluation of Performance

Journal of Chemical Information and Modeling, 2004

A molecular similarity searching technique based on Atom Environments, informationgain based feat... more A molecular similarity searching technique based on Atom Environments, informationgain based feature selection and the Naïve Bayesian Classifier has been applied to a series of diverse datasets and its performance compared to alternative searching methods.

Research paper thumbnail of Molecular Similarity Searching Using Atom Environments, Information-Based Feature Selection, and a Naïve Bayesian Classifier

Journal of Chemical Information and Modeling, 2004

A novel technique for similarity searching is introduced. Molecules are represented by atom envir... more A novel technique for similarity searching is introduced. Molecules are represented by atom environments, which are fed into an information-gain-based feature selection. A naïve Bayesian classifier is then employed for compound classification. The new method is tested by its ability to retrieve five sets of active molecules seeded in the MDL Drug Data Report (MDDR). In comparison experiments, the algorithm outperforms all current retrieval methods assessed here using two- and three-dimensional descriptors and offers insight into the significance of structural components for binding.

Research paper thumbnail of The challenges of in silico contributions to drug metabolism in lead optimization

Expert Opinion on Drug Metabolism & Toxicology, 2010

The site of metabolism (SOM) predictions by CYP 3A4 are extremely important during the drug disco... more The site of metabolism (SOM) predictions by CYP 3A4 are extremely important during the drug discovery process especially during the lead discovery or library design phases. With the ability to rapidly characterize metabolites from these enzymes, the challenges facing in silico contribution change during the drug optimization phase. Some of the challenges are addressed in this article. Some aspects of the SOM prediction software and methodology are discussed in this opinion article and examples of software utility in overcoming metabolic instability in drug optimization are shown. SOM prediction by various approaches is discussed. Two ways of overcoming metabolic instability, blocking the metabolic softspots and rational modification of the instable molecule to avoid interaction with the CYP pocket, are discussed. The contribution plot in MetaSite and its use are discussed. The reader will gain an understanding of possible approaches to either blocking the metabolic softspot or rationally modifying the molecule using MetaSite software or docking approaches. Blocking metabolism using fluorination has risks especially introducing multifluorinated benzene rings in the molecule. During the lead optimization phase of drug discovery, when metabolic instability is an issue in a series, in silico approaches can be used to modify the molecule in order to decrease clearance due to metabolism, even that due to CYP3A4.

Research paper thumbnail of Molecular dynamics simulations of the bulk phases of 4-cyano-4′-n-pentyloxybiphenyl

Research paper thumbnail of Discovery of covalent inhibitors for MIF tautomerase via cocrystal structures with phantom hits from virtual screening

Bioorganic & Medicinal Chemistry Letters, 2009

Biochemical and X-ray crystallographic studies confirmed that hydroxyquinoline derivatives identi... more Biochemical and X-ray crystallographic studies confirmed that hydroxyquinoline derivatives identified by virtual screening were actually covalent inhibitors of the MIF tautomerase. Adducts were formed by N-alkylation of the Pro-1 at the catalytic site with a loss of an amino group of the inhibitor.

Research paper thumbnail of On the mechanism of microsomal prostaglandin E synthase type-2—A theoretical study of endoperoxide reaction with MeS−

Bioorganic & Medicinal Chemistry Letters, 2010

Keywords: mPGES-2 enzyme PGES PGH2 PGE2 Ab initio calculations QM/MM Modeling Reaction mechanism ... more Keywords: mPGES-2 enzyme PGES PGH2 PGE2 Ab initio calculations QM/MM Modeling Reaction mechanism a b s t r a c t

Research paper thumbnail of Identification of optimum computational protocols for modeling the aryl hydrocarbon receptor (AHR) and its interaction with ligands

Bioorganic & Medicinal Chemistry Letters, 2010

The aryl hydrocarbon receptor (AHR) is one of the principal xenobiotic receptors in living organi... more The aryl hydrocarbon receptor (AHR) is one of the principal xenobiotic receptors in living organisms and is responsible for interacting with several drugs and environmental toxins, most notably tetrachlorodibenzodioxin (TCDD). Binding of diverse agonists to AHR initiates an extensive set of downstream gene expression responses and thus identifies AHR among a key set of proteins responsible for mediating interactions between living organisms and foreign molecules. While extensive biochemical investigations on the interaction of AHR with ligands have been carried out, studies comparing the abilities of specific computational algorithms in explaining the potency of known AHR ligands are lacking. In this study we use molecular dynamics simulations to identify a physically realistic conformation of the AHR that is relevant to ligand binding. We then use two sets of existing data on known AHR ligands to evaluate the performance of several docking and scoring protocols in rationalizing the potencies of these ligands. The results identify an optimum set of protocols that could prove useful in future AHR ligand discovery and design as a target or anti-target. Exploration of the details of these protocols sheds light on factors operating in modeling AHR ligand binding.

Research paper thumbnail of Texture mapping: A new tool for molecular graphics

Journal of Molecular Graphics, 1994

The real-time texture mapping capabilities of modern graphics workstations are explored with resp... more The real-time texture mapping capabilities of modern graphics workstations are explored with respect to their applications in a variety of relevant scenarios in interactive molecular modeling techniques. The common usage of texture mapping to reduce geometric complexity while enhancing realism is extended, opening new ways to visualize large amounts of molecular data in a comprehensive fashion. Thus, texture mapping may be employed to (I) display and filter multichannel information of structural properties on molecular sur$aces, (2) improve the quality and accuracy of highly complex isodensity contours, (3) increase the rendering speed of space-filling atomic representations by two orders of magnitude and (4) apply volume-rendering techniques to large, three-dimensional density distributions in real time. Implementation of these novel techniques requires only moderate modtfications or extensions to existing molecular modeling applications.

Research paper thumbnail of Theoretical investigations on the structure and physical properties of cellulose

Research paper thumbnail of A novel computational method for comparing vibrational circular dichroism spectra

Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy, 2010

A novel method, SimIR/VCD, for comparing experimental and calculated VCD (vibrational circular di... more A novel method, SimIR/VCD, for comparing experimental and calculated VCD (vibrational circular dichroism) spectra is developed, based on newly defined spectra similarities. With computationally optimized frequency scaling and shifting, a calculated spectrum can be easily identified to match an observed spectrum, which leads to an unbiased molecular chirality assignment. The time-consuming manual band-fitting work is greatly reduced. With (1S)-(-)-alpha-pinene as an example, it demonstrates that the calculated VCD similarity is correlated with VCD spectra matching quality and has enough sensitivity to identify variations in the spectra. The study also compares spectra calculated using different DFT methods and basis sets. Using this method should facilitate the spectra matching, reduce human error and provide a confidence measure in the chiral assignment using VCD spectroscopy.

Research paper thumbnail of Prediction of the 3D Structure and Dynamics of Human DP G-Protein Coupled Receptor Bound to an Agonist and an Antagonist

Journal of the American Chemical Society, 2007

Prostanoids play important physiological roles in the cardiovascular and immune systems and in pa... more Prostanoids play important physiological roles in the cardiovascular and immune systems and in pain sensation in peripheral systems through their interactions with eight G-Protein Coupled Receptors. These receptors are important drug targets, but development of subtype specific agonists and antagonists has been hampered by the lack of 3D structures for these receptors. We report here the 3D structure for the human DP G-Protein Coupled Receptor (GPCR) predicted by the MembStruk computational method. To validate this structure we use the HierDock computational method to predict the binding mode for the endogenous agonist (PGD2) to DP. Based on our structure, we predicted the binding of a new family of antagonists which has been confirmed experimentally.

Research paper thumbnail of Similarity Searching of Chemical Databases Using Atom Environment Descriptors (MOLPRINT 2D): Evaluation of Performance

Journal of Chemical Information and Modeling, 2004

A molecular similarity searching technique based on Atom Environments, informationgain based feat... more A molecular similarity searching technique based on Atom Environments, informationgain based feature selection and the Naïve Bayesian Classifier has been applied to a series of diverse datasets and its performance compared to alternative searching methods.

Research paper thumbnail of Molecular Similarity Searching Using Atom Environments, Information-Based Feature Selection, and a Naïve Bayesian Classifier

Journal of Chemical Information and Modeling, 2004

A novel technique for similarity searching is introduced. Molecules are represented by atom envir... more A novel technique for similarity searching is introduced. Molecules are represented by atom environments, which are fed into an information-gain-based feature selection. A naïve Bayesian classifier is then employed for compound classification. The new method is tested by its ability to retrieve five sets of active molecules seeded in the MDL Drug Data Report (MDDR). In comparison experiments, the algorithm outperforms all current retrieval methods assessed here using two- and three-dimensional descriptors and offers insight into the significance of structural components for binding.

Research paper thumbnail of The challenges of in silico contributions to drug metabolism in lead optimization

Expert Opinion on Drug Metabolism & Toxicology, 2010

The site of metabolism (SOM) predictions by CYP 3A4 are extremely important during the drug disco... more The site of metabolism (SOM) predictions by CYP 3A4 are extremely important during the drug discovery process especially during the lead discovery or library design phases. With the ability to rapidly characterize metabolites from these enzymes, the challenges facing in silico contribution change during the drug optimization phase. Some of the challenges are addressed in this article. Some aspects of the SOM prediction software and methodology are discussed in this opinion article and examples of software utility in overcoming metabolic instability in drug optimization are shown. SOM prediction by various approaches is discussed. Two ways of overcoming metabolic instability, blocking the metabolic softspots and rational modification of the instable molecule to avoid interaction with the CYP pocket, are discussed. The contribution plot in MetaSite and its use are discussed. The reader will gain an understanding of possible approaches to either blocking the metabolic softspot or rationally modifying the molecule using MetaSite software or docking approaches. Blocking metabolism using fluorination has risks especially introducing multifluorinated benzene rings in the molecule. During the lead optimization phase of drug discovery, when metabolic instability is an issue in a series, in silico approaches can be used to modify the molecule in order to decrease clearance due to metabolism, even that due to CYP3A4.

Research paper thumbnail of Molecular dynamics simulations of the bulk phases of 4-cyano-4′-n-pentyloxybiphenyl

Research paper thumbnail of Discovery of covalent inhibitors for MIF tautomerase via cocrystal structures with phantom hits from virtual screening

Bioorganic & Medicinal Chemistry Letters, 2009

Biochemical and X-ray crystallographic studies confirmed that hydroxyquinoline derivatives identi... more Biochemical and X-ray crystallographic studies confirmed that hydroxyquinoline derivatives identified by virtual screening were actually covalent inhibitors of the MIF tautomerase. Adducts were formed by N-alkylation of the Pro-1 at the catalytic site with a loss of an amino group of the inhibitor.

Research paper thumbnail of On the mechanism of microsomal prostaglandin E synthase type-2—A theoretical study of endoperoxide reaction with MeS−

Bioorganic & Medicinal Chemistry Letters, 2010

Keywords: mPGES-2 enzyme PGES PGH2 PGE2 Ab initio calculations QM/MM Modeling Reaction mechanism ... more Keywords: mPGES-2 enzyme PGES PGH2 PGE2 Ab initio calculations QM/MM Modeling Reaction mechanism a b s t r a c t

Research paper thumbnail of Identification of optimum computational protocols for modeling the aryl hydrocarbon receptor (AHR) and its interaction with ligands

Bioorganic & Medicinal Chemistry Letters, 2010

The aryl hydrocarbon receptor (AHR) is one of the principal xenobiotic receptors in living organi... more The aryl hydrocarbon receptor (AHR) is one of the principal xenobiotic receptors in living organisms and is responsible for interacting with several drugs and environmental toxins, most notably tetrachlorodibenzodioxin (TCDD). Binding of diverse agonists to AHR initiates an extensive set of downstream gene expression responses and thus identifies AHR among a key set of proteins responsible for mediating interactions between living organisms and foreign molecules. While extensive biochemical investigations on the interaction of AHR with ligands have been carried out, studies comparing the abilities of specific computational algorithms in explaining the potency of known AHR ligands are lacking. In this study we use molecular dynamics simulations to identify a physically realistic conformation of the AHR that is relevant to ligand binding. We then use two sets of existing data on known AHR ligands to evaluate the performance of several docking and scoring protocols in rationalizing the potencies of these ligands. The results identify an optimum set of protocols that could prove useful in future AHR ligand discovery and design as a target or anti-target. Exploration of the details of these protocols sheds light on factors operating in modeling AHR ligand binding.

Research paper thumbnail of Texture mapping: A new tool for molecular graphics

Journal of Molecular Graphics, 1994

The real-time texture mapping capabilities of modern graphics workstations are explored with resp... more The real-time texture mapping capabilities of modern graphics workstations are explored with respect to their applications in a variety of relevant scenarios in interactive molecular modeling techniques. The common usage of texture mapping to reduce geometric complexity while enhancing realism is extended, opening new ways to visualize large amounts of molecular data in a comprehensive fashion. Thus, texture mapping may be employed to (I) display and filter multichannel information of structural properties on molecular sur$aces, (2) improve the quality and accuracy of highly complex isodensity contours, (3) increase the rendering speed of space-filling atomic representations by two orders of magnitude and (4) apply volume-rendering techniques to large, three-dimensional density distributions in real time. Implementation of these novel techniques requires only moderate modtfications or extensions to existing molecular modeling applications.