Eugene M. Fluder

Bio: Eugene M. Fluder is an academic researcher from Merck & Co.. The author has contributed to research in topics: Chemical similarity & Latent semantic structure indexing. The author has an hindex of 13, co-authored 21 publications receiving 2170 citations.

Chemical similarity using physiochemical property descriptors

Abstract: Similarity searches using topological descriptors have proved extremely useful in aiding large-scale screening. We describe alternative forms of the atom pair (Carhart et al. J. Chem. Inf. Comput. Sci. 1985, 25, 64−73.) and topological torsion (Nilakantan et al. J. Chem. Inf. Comput. Sci. 1987, 27, 82−85.) descriptors that use physiochemical atom types. These types are based on binding property class, atomic log P contribution, and partial atomic charges. The new descriptors are meant to be more “fuzzy” than the original descriptors. We propose objective criteria for determining how effective one descriptor is versus another in selecting active compounds from large databases. Using these criteria, we run similarity searches over the Derwent Standard Drug File with ten typical druglike probes. The new descriptors are not as good as the original descriptors in selecting actives if one considers the average over all probes, but the new descriptors do better for several individual probes. Generally we find th...

Text influenced molecular indexing system and computer-implemented and/or computer-assisted method for same

Abstract: An extension of the vector space model for computing chemical similarity using textual and chemical descriptors is described. The method uses a chemical and/or textual description of a molecule/chemical and a decomposes a molecule/chemical descriptor matrix by a suitable technique such as singular value decomposition to create a low dimensional representation of the original descriptor space. Similarities between a user probe and the textual and/or chemical descriptors are then computed and ranked.

Tautomerization of formamide, 2-pyridone, and 4-pyridone: an ab initio study

Abstract: The tautomerism of formamide, 2-pyridone, and 4-pyridone has been investigated by ab initio calculations using minimal, extended, and polarization basis sets. When the effects of geometry optimization, polarization functions, correlation energy (estimated by second-order Merller-Plesset perturbation theory), and zero-point vibration energy are combined, the following theoretical estimates are obtained: formimidic acid is 12 kcal/mol less stable than formamide, 2-pyridone is 0.3 kcal/mol more stable than 2-hydroxypyridine and 4-hydroxypyridine is 2.4 kcal/mol more stable than 4-pyridone. Only the 2-pyridone tautomerism has been observed directly in the gas phase, and theory is in good agreement with all three experimental values (0.3 f 0.3,O.l & 0.6,0.6 f 0.1 kcal/mol). In the case of 4-pyridone, the theoretical value may be closer to the actual tautomerization energy than the 7 kcal/mol in favor of hydroxypyridine obtained from indirect experiments. For the heterocycles, relative geometries of tautomers optimized with a minimal basis or semiempirical methods are as satisfactory as structural changes obtained at extended basis set levels. Relative tautomerization energies are reproduced well with the minimal or extended bases, while absolute tautomerization energies require consideration of polarization functions, correlation energy, and zero-point vibration. Tautomerism such as displayed by pyridone/hydroxypyridine plays a role in many areas of chemistry and biochemistry: e.g., the rationalization of structures, properties, and reactivities in heterocyclic chemistry;'*2 concepts and probes of aromaticity;3 measures of intrinsic stabilities vs. solvent mechanisms of enzymatic catalysis and receptor interactions;6 and possibly even mutations during DNA replicati~n.~.~ Investigations of tautom- erism of 2-pyridone date from 1907.8 Most studies since then have dealt with the equilibrium in liquid media,'v9 where the pyridone tautomer is preferred by a factor of 1000. X-ray crystallography shows that pyridone is also favored in the solid.'*I2 The dominance of the pyridone tautomer in solution, neat liquid, and solids has been shown to be the result of strong solvent effects, ion binding, and self- association^.'^^^^^^^'^ In contrast, recent IR and UV measurements have established that the two tautomers are nearly equal in energy when unassociated in the vap~r.~,'~J~ Similar gas-phase tautomerizations have since been investigated for a number of lactam/lactim pairs by using IR,I9 UV,zo pho- toelectron,21*22 ion cyclotron resonan~e,~~-~~ and mass spectros- copy.26*27 All of these gas-phase equilibria show marked dif- ferences from solution data.'*2,9,'3-'7*z8 Numerous theoretical studies with almost every available method have attempted to reproduce the tautomerization energy for pyridone/hydroxypyridine and similar heterocyclic systems2- Simulations of hydrogen bonding and solvent interactions re- produce qualitatively the shift in the equilibrium toward pyridone in condensed However, quantitative agreement with the tautomerization energy in the vapor has been difficult to obtain. Geometry optimization, basis-set flexibility, correlation energy, and zero-point vibration have been recognized as important contributors to these and related45-55 isomerization reactions. In this paper, we report an extensive series of ab initio computations on formamide, 2-pyridone, 4-pyridone, and their tautomers that take these factors into account. Method Ab initio calculations were carried out with the GAUSSIANBO series of programss6 by using minimal (STO-3G)," extended(3-21G and 6- 31G),5*~~~ and polarization (6-31G*)" basis sets. The extended basis sets are of the split-valence. type, and the polarization basis set is an extended basis augmented by a shell of six Cartesian d-type Gaussians on each non-hydrogen atom. Energies were calculated in the Hartree-Fock (HF) approximation, and correlation effects were estimated via second-order

Protocols for bridging the peptide to nonpeptide gap in topological similarity searches.

Abstract: Similarity searches based on chemical descriptors have proven extremely useful in aiding large-scale drug screening. Typically an investigator starts with a “probe”, a drug-like molecule with an interesting biological activity, and searches a database to find similar compounds. In some projects, however, the only known actives are peptides, and the investigator needs to identify drug-like actives. 3D similarity methods are able to help in this endeavor but suffer from the necessity of having to specify the active conformation of the probe, something that is not always possible at the beginning of a project. Also, 3D methods are slow and are complicated by the need to generate low-energy conformations. In contrast, topological methods are relatively rapid and do not depend on conformation. However, unmodified topological similarity methods, given a peptide probe, will preferentially select other peptides from a database. In this paper we show some simple protocols that, if used with a standard topological ...

The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans

Abstract: Understanding the functional consequences of genetic variation, and how it affects complex human disease and quantitative traits, remains a critical challenge for biomedicine. We present an analysi...

Neuroinflammation in Alzheimer's disease

Abstract: Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that increase the risk for sporadic Alzheimer's disease encode factors that regulate glial clearance of misfolded proteins and the inflammatory reaction. External factors, including systemic inflammation and obesity, are likely to interfere with immunological processes of the brain and further promote disease progression. Modulation of risk factors and targeting of these immune mechanisms could lead to future therapeutic or preventive strategies for Alzheimer's disease.

The amyloid hypothesis of Alzheimer's disease at 25 years

Abstract: Despite continuing debate about the amyloid β‐protein (or Aβ hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and clearance of Aβ42 and related Aβ peptides is a very early, often initiating factor in Alzheimer9s disease (AD). Confirmation that presenilin is the catalytic site of γ‐secretase has provided a linchpin: all dominant mutations causing early‐onset AD occur either in the substrate (amyloid precursor protein, APP) or the protease (presenilin) of the reaction that generates Aβ. Duplication of the wild‐type APP gene in Down9s syndrome leads to Aβ deposits in the teens, followed by microgliosis, astrocytosis, and neurofibrillary tangles typical of AD. Apolipoprotein E4, which predisposes to AD in > 40% of cases, has been found to impair Aβ clearance from the brain. Soluble oligomers of Aβ42 isolated from AD patients9 brains can decrease synapse number, inhibit long‐term potentiation, and enhance long‐term synaptic depression in rodent hippocampus, and injecting them into healthy rats impairs memory. The human oligomers also induce hyperphosphorylation of tau at AD‐relevant epitopes and cause neuritic dystrophy in cultured neurons. Crossing human APP with human tau transgenic mice enhances tau‐positive neurotoxicity. In humans, new studies show that low cerebrospinal fluid (CSF) Aβ42 and amyloid‐PET positivity precede other AD manifestations by many years. Most importantly, recent trials of three different Aβ antibodies (solanezumab, crenezumab, and aducanumab) have suggested a slowing of cognitive decline in post hoc analyses of mild AD subjects. Although many factors contribute to AD pathogenesis, Aβ dyshomeostasis has emerged as the most extensively validated and compelling therapeutic target.

Singular Value Decomposition for Genome-Wide Expression Data Processing and Modeling

Abstract: ‡We describe the use of singular value decomposition in transforming genome-wide expression data from genes 3 arrays space to reduced diagonalized ‘‘eigengenes’’ 3 ‘‘eigenarrays’’ space, where the eigengenes (or eigenarrays) are unique orthonormal superpositions of the genes (or arrays). Normalizing the data by filtering out the eigengenes (and eigenarrays) that are inferred to represent noise or experimental artifacts enables meaningful comparison of the expression of different genes across different arrays in different experiments. Sorting the data according to the eigengenes and eigenarrays gives a global picture of the dynamics of gene expression, in which individual genes and arrays appear to be classified into groups of similar regulation and function, or similar cellular state and biological phenotype, respectively. After normalization and sorting, the significant eigengenes and eigenarrays can be associated with observed genome-wide effects of regulators, or with measured samples, in which these regulators are overactive or underactive, respectively.

Chemical Similarity Searching

Abstract: This paper reviews the use of similarity searching in chemical databases. It begins by introducing the concept of similarity searching, differentiating it from the more common substructure searching, and then discusses the current generation of fragment-based measures that are used for searching chemical structure databases. The next sections focus upon two of the principal characteristics of a similarity measure: the coefficient that is used to quantify the degree of structural resemblance between pairs of molecules and the structural representations that are used to characterize molecules that are being compared in a similarity calculation. New types of similarity measure are then compared with current approaches, and examples are given of several applications that are related to similarity searching.