Jay T. Goodwin
Emory University
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Featured researches published by Jay T. Goodwin.
Journal of Pharmacology and Experimental Therapeutics | 2002
Philip S. Burton; Jay T. Goodwin; Thomas J. Vidmar; Benny M. Amore
Significant recent work has focused on predicting drug absorption from structure. Several misperceptions regarding the nature of absorption seem to be common. Among these is that intestinal absorption, permeability, fraction absorbed, and, in some cases, even bioavailability, are equivalent properties and can be used interchangeably. A second common misperception is that absorption, permeability, etc. are discrete, fundamental properties of the molecule and can be predicted solely from some structural representation of the drug. In reality, drug absorption is a complex process dependent upon drug properties such as solubility and permeability, formulation factors, and physiological variables, including regional permeability differences, pH, lumenal and mucosal enzymology, and intestinal motility, among others. This article will explore the influence of these different variables on drug absorption and the implications with regards to attempting to develop predictive drug absorption algorithms.
Tetrahedron Letters | 1993
Jay T. Goodwin; Gary D. Glick
Ab#nu~ A saics of alkylthiol-tether homologs at C-5 of 2’-deoxyuddin~ have bceo qmthebd and i 7zEz inm DNA oligomm Wough solid-phase DNA pmtc synth&s. DNA-IigawJ disuitlde cmssbks initially &drwsed through fmnation of an n-butyl-DNA disublde conjuSate.
Advanced Drug Delivery Reviews | 1997
Philip S. Burton; Jay T. Goodwin; Robert A. Conradi; Norman F.H. Ho; Allen R. Hilgers
Abstract Cellular efflux pathways function to remove both endogenous and exogenous substances from the cell. In the case of a polarized cellular barrier, such as the epithelium, these pathways serve an excretory or secretory role in transporting solutes out of tissue. Although well recognized in organs typically associated with drug excretion such as liver and kidney, similar transport pathways have been found in other tissues including the intestinal mucosa and the endothelial cells comprising the blood-brain barrier. Current evidence suggests that these systems may act as barriers to drug absorption into the tissues in which they are found. More recent studies have shown that hydrophobic peptides such as cyclosporin A are substrates for polarized efflux. In this review we examine the evidence for these mechanisms as absorption barriers and the use of in vitro transport models for characterizing this phenomenon. The presence of such pathways may help explain the poor membrane permeability of peptides which, along with metabolism, contributes to their poor in vivo performance.
Accounts of Chemical Research | 2012
Jay T. Goodwin; Anil K. Mehta; David G. Lynn
Living matter is the most elaborate, elegant, and complex hierarchical material known and is consequently the natural target for an ever-expanding scientific and technological effort to unlock and deconvolute its marvelous forms and functions. Our current understanding suggests that biological materials are derived from a bottom-up process, a spontaneous emergence of molecular networks in the course of chemical evolution. Polymer cooperation, so beautifully manifested in the ribosome, appeared in these dynamic networks, and the special physicochemical properties of the nucleic and amino acid polymers made possible the critical threshold for the emergence of extant cellular life. These properties include the precise and geometrically discrete hydrogen bonding patterns that dominate the complementary interactions of nucleic acid base-pairing that guide replication and ensure replication fidelity. In contrast, complex and highly context-dependent sets of intra- and intermolecular interactions guide protein folding. These diverse interactions allow the more analog environmental chemical potential fluctuations to dictate conformational template-directed propagation. When these two different strategies converged in the remarkable synergistic ribonucleoprotein that is the ribosome, this resulting molecular digital-to-analog converter achieved the capacity for both persistent information storage and adaptive responses to an ever-changing environment. The ancestral chemical networks that preceded the Central Dogma of Earths biology must reflect the dynamic chemical evolutionary landscapes that allowed for selection, propagation, and diversification and ultimately the demarcation and specialization of function that modern biopolymers manifest. Not only should modern biopolymers contain molecular fossils of this earlier age, but it should be possible to use this information to reinvent these dynamic functional networks. In this Account, we review the first dynamic network created by modification of a nucleic acid backbone and show how it has exploited the digital-like base pairing for reversible polymer construction and information transfer. We further review how these lessons have been extended to the complex folding landscapes of templated peptide assembly. These insights have allowed for the construction of molecular hybrids of each biopolymer class and made possible the reimagining of chemical evolution. Such elaboration of biopolymer chimeras has already led to applications in therapeutics and diagnostics, to the construction of novel nanostructured materials, and toward orthogonal biochemical pathways that expand the evolution of existing biochemical systems. The ability to look beyond the primordial emergence of the ribosome may allow us to better define the origins of chemical evolution, to extend its horizons beyond the biology of today and ask whether evolution is an inherent property of matter unbounded by physical limitations imposed by our planets diverse environments.
Tetrahedron Letters | 1994
Jay T. Goodwin; Gary D. Glick
Abstract An N -3 ethylthiol-modified uridine has been synthesized and incorporated through solid-phase phosphoramidite chemistry at the 5′- and 3′-termini of an RNA hairpin to provide increased conformational stability via a disulfide cross-link.
Nature Chemistry | 2017
Chenrui Chen; Junjun Tan; Ming-Chien Hsieh; Ting Pan; Jay T. Goodwin; Anil Mehta; Martha A. Grover; David G. Lynn
Template-directed polymerization reactions enable the accurate storage and processing of natures biopolymer information. This mutualistic relationship of nucleic acids and proteins, a network known as lifes central dogma, is now marvellously complex, and the progressive steps necessary for creating the initial sequence and chain-length-specific polymer templates are lost to time. Here we design and construct dynamic polymerization networks that exploit metastable prion cross-β phases. Mixed-phase environments have been used for constructing synthetic polymers, but these dynamic phases emerge naturally from the growing peptide oligomers and create environments suitable both to nucleate assembly and select for ordered templates. The resulting templates direct the amplification of a phase containing only chain-length-specific peptide-like oligomers. Such multi-phase biopolymer dynamics reveal pathways for the emergence, self-selection and amplification of chain-length- and possibly sequence-specific biopolymers.
Biopolymers | 2000
David A. Kloosterman; Jay T. Goodwin; Philip S. Burton; Robert A. Conradi; Brian J. Stockman; Terrence A. Scahill; James R. Blinn
Efficient transport of intact drug (solute) across the intestinal epithelium is typically a requirement for good oral activity. In general, the membrane permeability of a solute is a complex function of its size, lipophilicity, hydrogen bond potential, charge, and conformation. In conjunction with theoretical/computational and in vitro drug transport studies, seven dipeptide (R1–D‐Xaa–D‐Phe–NHMe) homologues were each dissolved in a micellar d38‐dodecylphosphocholine solvent system. In this homologous dipeptide series, factors such as size, lipophilicity, hydrogen‐bond potential, and charge were either tightly controlled or well‐characterized by other methods in order to investigate by nmr how conformational factors relate to transport. Nuclear Overhauser effect spectroscopy experiments and amide‐NH–H2O chemical exchange rates showed that the five more lipophilic dipeptides were predominately associated with micelle, whereas the two less lipophilic analogues were not. Rotating frame nuclear Overhauser effect spectroscopy derived interproton distance restraints for each analogue, along with 3JHH‐derived dihedral restraints, were used in molecular dynamics/simulated annealing computations. Our results suggest that—other factors being equal—flexible dipeptides having a propensity to fold together nonpolar N‐ and C‐terminal moieties allow greater segregation of polar and nonpolar domains and may possess enhanced transport characteristics. Dipeptides that were less flexible or that retained a less amphiphilic conformation did not have comparably enhanced transport characteristics. We suggest that these conformational/transport correlations may hold true for small, highly functionalized solutes (drugs) in general.
Combinatorial Chemistry & High Throughput Screening | 2010
Philip S. Burton; Jay T. Goodwin
Solubility and cellular permeability are two of the most important biopharmaceutical properties impacting the successful development of drug substances. Given the importance of these properties, most pharmaceutical companies have invested in medium to high throughput technologies for early evaluation of these characteristics in the drug discovery funnel in order to select, prioritize or eliminate compounds with unfavorable solubility and/or permeability. However, these technologies require physical samples of the substances to be tested. In order to facilitate the early stages of drug discovery, such as defining compound collection composition, designing combinatorial libraries, and in hit expansion or lead optimization, models for predicting aqueous solubility and permeability in the absence of physical sample are increasingly being employed. In this overview, we will discuss solubility and permeability experimental and computational methods separately and then interrelate them in physiologically relevant models for predicting in vivo performance.
Astrobiology | 2015
H. James Cleaves; Markus Meringer; Jay T. Goodwin
Abstract Ribonucleic acid (RNA) is one of the two nucleic acids used by extant biochemistry and plays a central role as the intermediary carrier of genetic information in transcription and translation. If RNA was involved in the origin of life, it should have a facile prebiotic synthesis. A wide variety of such syntheses have been explored. However, to date no one-pot reaction has been shown capable of yielding RNA monomers from likely prebiotically abundant starting materials, though this does not rule out the possibility that simpler, more easily prebiotically accessible nucleic acids may have preceded RNA. Given structural constraints, such as the ability to form complementary base pairs and a linear covalent polymer, a variety of structural isomers of RNA could potentially function as genetic platforms. By using structure-generation software, all the potential structural isomers of the ribosides (BC5H9O4, where B is nucleobase), as well as a set of simpler minimal analogues derived from them, that can potentially serve as monomeric building blocks of nucleic acid–like molecules are enumerated. Molecules are selected based on their likely stability under biochemically relevant conditions (e.g., moderate pH and temperature) and the presence of at least two functional groups allowing the monomers to be incorporated into linear polymers. The resulting structures are then evaluated by using molecular descriptors typically applied in quantitative structure–property relationship (QSPR) studies and predicted physicochemical properties. Several databases have been queried to determine whether any of the computed isomers had been synthesized previously. Very few of the molecules that emerge from this structure set have been previously described. We conclude that ribonucleosides may have competed with a multitude of alternative structures whose potential proto-biochemical roles and abiotic syntheses remain to be explored. Key Words: Evolution—Chemical evolution—Exobiology—Prebiotic chemistry—RNA world. Astrobiology 15, 538–558.
Tetrahedron Letters | 1994
Jay T. Goodwin; Scott E. Osborne; Patrick C. Swanson; Gary D. Glick
An intramolecular DNA triple helix incorporating a disulfide cross-link has been synthesized. Potassium permanganate footprinting and UV melting analysis demonstrate that the cross-link increases the conformational stability of this novel triplex at physiological pH and [Mg2+] relative to the unmodified sequence.