Author
George Chang
Bio: George Chang is an academic researcher from Pfizer. The author has contributed to research in topics: Microsomal triglyceride transfer protein & Apolipoprotein B. The author has an hindex of 22, co-authored 64 publications receiving 6427 citations.
Papers published on a yearly basis
Papers
More filters
TL;DR: An integrated molecular modeling system for designing and studying organic and bioorganic molecules and their molecular complexes using molecular mechanics is described in this article, which allows the construction, display and manipulation of molecules and complexes having as many as 10,000 atoms and provides interactive, state-of-the-art molecular mechanics on any subset of up to 1000 atoms.
Abstract: An integrated molecular modeling system for designing and studying organic and bioorganic molecules and their molecular complexes using molecular mechanics is described. The graphically controlled, atom-based system allows the construction, display and manipulation of molecules and complexes having as many as 10,000 atoms and provides interactive, state-of-the-art molecular mechanics on any subset of up to 1,000 atoms. The system semiautomates the graphical construction and analysis of complex structures ranging from polycyclic organic molecules to biopolymers to mixed molecular complexes. We have placed emphasis on providing effective searches of conformational space by a number of different methods and on highly optimized molecular mechanics energy calculations using widely used force fields which are supplied as external files. Little experience is required to operate the system effectively and even novices can use it to carry out sophisticated modeling operations. The software has been designed to run on Digital Equipment Corporation VAX computers interfaced to a variety of graphics devices ranging from inexpensive monochrome terminals to the sophisticated graphics displays of the Evans & Sutherland PS300 series.
3,507 citations
TL;DR: In this article, an internal coordinate random-search method for finding low-energy conformations of organic molecules is described, which is biased toward the low energy regions of conformational space by choosing starting geometries for each step in the conformational search.
Abstract: An internal coordinate, random-search method for finding the low-energy conformations of organic molecules is described. The search is biased toward the low-energy regions of conformational space by choosing starting geometries for each step in the conformational search from among previously stored low-energy conformers. Tendencies of the search method to concentrate in certain regions of conformational space at the expense of others are reduced by uniform usage of stored structures as starting geometries and by using varying numbers or torsional rotations in each step. Tests of the procedure's ability to find all low-energy conformations of several acrylic, medium- and large-ring molecules are described. Direct comparisons of the method with Cartesian coordinate random methods and systematic internal coordinate grid searches are carried out with symmetrical and unsymmetrical molecules. The method makes it possible to carry out global conformational searches on symmetrical and unsymmetrical molecules having up to a dozen variable torsion angles.
1,050 citations
479 citations
TL;DR: In conclusion, physicochemical properties influence bioavailability with typically opposing effects on Fa and first-pass elimination, which may provide a rational judgment on the physicochemical space to optimize oral bioavailability.
Abstract: Oral bioavailability (F) is a product of fraction absorbed (Fa), fraction escaping gut-wall elimination (Fg), and fraction escaping hepatic elimination (Fh). In this study, using a database comprised of Fa, Fg, Fh, and F values for 309 drugs in humans, an analysis of the interrelation of physicochemical properties and the individual parameters was carried out in order to define the physicochemical space for optimum human oral bioavailability. Trend analysis clearly indicated molecular weight (MW), ionization state, lipophilicity, polar descriptors, and free rotatable bonds (RB) influence bioavailability. These trends were due to a combination of effects of the properties on Fa and first-pass elimination (Fg and Fh). Higher MW significantly impacted Fa, while Fg and Fh decreased with increasing lipophilicity. Parabolic trends were observed for bioavailability with polar descriptors. Interestingly, RB has a negative effect on all three parameters, leading to its pronounced effect on bioavailability. In conclusion, physicochemical properties influence bioavailability with typically opposing effects on Fa and first-pass elimination. This analysis may provide a rational judgment on the physicochemical space to optimize oral bioavailability.
240 citations
TL;DR: When administered as a single oral dose to healthy human volunteers, CP-346086 reduced plasma triglycerides and VLDL cholesterol dose dependently with ED50s of 10 mg and 3 mg, and maximal inhibition of 66% and 87% when measured 4 h after treatment.
188 citations
Cited by
More filters
TL;DR: A general Amber force field for organic molecules is described, designed to be compatible with existing Amber force fields for proteins and nucleic acids, and has parameters for most organic and pharmaceutical molecules that are composed of H, C, N, O, S, P, and halogens.
Abstract: We describe here a general Amber force field (GAFF) for organic molecules. GAFF is designed to be compatible with existing Amber force fields for proteins and nucleic acids, and has parameters for most organic and pharmaceutical molecules that are composed of H, C, N, O, S, P, and halogens. It uses a simple functional form and a limited number of atom types, but incorporates both empirical and heuristic models to estimate force constants and partial atomic charges. The performance of GAFF in test cases is encouraging. In test I, 74 crystallographic structures were compared to GAFF minimized structures, with a root-mean-square displacement of 0.26 A, which is comparable to that of the Tripos 5.2 force field (0.25 A) and better than those of MMFF 94 and CHARMm (0.47 and 0.44 A, respectively). In test II, gas phase minimizations were performed on 22 nucleic acid base pairs, and the minimized structures and intermolecular energies were compared to MP2/6-31G* results. The RMS of displacements and relative energies were 0.25 A and 1.2 kcal/mol, respectively. These data are comparable to results from Parm99/RESP (0.16 A and 1.18 kcal/mol, respectively), which were parameterized to these base pairs. Test III looked at the relative energies of 71 conformational pairs that were used in development of the Parm99 force field. The RMS error in relative energies (compared to experiment) is about 0.5 kcal/mol. GAFF can be applied to wide range of molecules in an automatic fashion, making it suitable for rational drug design and database searching.
13,615 citations
Journal Article•
TL;DR: This book by a teacher of statistics (as well as a consultant for "experimenters") is a comprehensive study of the philosophical background for the statistical design of experiment.
Abstract: THE DESIGN AND ANALYSIS OF EXPERIMENTS. By Oscar Kempthorne. New York, John Wiley and Sons, Inc., 1952. 631 pp. $8.50. This book by a teacher of statistics (as well as a consultant for \"experimenters\") is a comprehensive study of the philosophical background for the statistical design of experiment. It is necessary to have some facility with algebraic notation and manipulation to be able to use the volume intelligently. The problems are presented from the theoretical point of view, without such practical examples as would be helpful for those not acquainted with mathematics. The mathematical justification for the techniques is given. As a somewhat advanced treatment of the design and analysis of experiments, this volume will be interesting and helpful for many who approach statistics theoretically as well as practically. With emphasis on the \"why,\" and with description given broadly, the author relates the subject matter to the general theory of statistics and to the general problem of experimental inference. MARGARET J. ROBERTSON
13,333 citations
TL;DR: An integrated molecular modeling system for designing and studying organic and bioorganic molecules and their molecular complexes using molecular mechanics is described in this article, which allows the construction, display and manipulation of molecules and complexes having as many as 10,000 atoms and provides interactive, state-of-the-art molecular mechanics on any subset of up to 1000 atoms.
Abstract: An integrated molecular modeling system for designing and studying organic and bioorganic molecules and their molecular complexes using molecular mechanics is described. The graphically controlled, atom-based system allows the construction, display and manipulation of molecules and complexes having as many as 10,000 atoms and provides interactive, state-of-the-art molecular mechanics on any subset of up to 1,000 atoms. The system semiautomates the graphical construction and analysis of complex structures ranging from polycyclic organic molecules to biopolymers to mixed molecular complexes. We have placed emphasis on providing effective searches of conformational space by a number of different methods and on highly optimized molecular mechanics energy calculations using widely used force fields which are supplied as external files. Little experience is required to operate the system effectively and even novices can use it to carry out sophisticated modeling operations. The software has been designed to run on Digital Equipment Corporation VAX computers interfaced to a variety of graphics devices ranging from inexpensive monochrome terminals to the sophisticated graphics displays of the Evans & Sutherland PS300 series.
3,507 citations
TL;DR: Three kinds of algorithms that learn axis-parallel rectangles to solve the multiple instance problem are described and compared, giving 89% correct predictions on a musk odor prediction task.
2,767 citations
TL;DR: The Pharmacological Basis of Therapeutics, by Prof. Louis Goodman and Prof. Alfred Gilman, New York: The Macmillan Company, 1941, p.
Abstract: The Pharmacological Basis of Therapeutics A Textbook of Pharmacology, Toxicology and Therapeutics for Physicians and Medical Students. By Prof. Louis Goodman and Prof. Alfred Gilman. Pp. xiii + 1383. (New York: The Macmillan Company, 1941.) 50s. net.
2,686 citations