Gerald Lushington - Profile on Academia.edu (original) (raw)
Papers by Gerald Lushington
Comparative Modeling of Proteins
Methods in molecular biology, 2008
Three-dimensional analysis of protein structures is proving to be one of the most fruitful modes ... more Three-dimensional analysis of protein structures is proving to be one of the most fruitful modes of biological and medical discovery in the early 21st century, providing fundamental insight into many (perhaps most) biochemical functions of relevance to the cause and treatment of diseases. Fully realizing such insight, however, would require analysis of too many distinct proteins for thorough laboratory analysis of all proteins to be feasible, thus, any method capable of accurate, efficient in silico structure prediction should prove highly expeditious. The technique generally acknowledged to provide the most accurate protein structure predictions, called comparative modeling, has, thus, attracted substantial attention and is the focus of this chapter. Although other reviews have reported on the method development and research history of comparative modeling, our discussion herein focuses on the general philosophy of the method and specific strategies for successfully achieving reliable and accurate models. The chapter, thus, relates aspects of template selection, sequence alignment, spatial alignment, loop and gap modeling, side chain modeling, structural refinement, and validation.
Synthesis of Diverse Library of 1,2-Dihydroisoquinolines Based on a Lewis Organocatalyst-Cocatalyzed Multicomponent Reaction of 2-(1-Alkynyl)Benzaldehydes, Amines and Ketones
For decades, a great deal of public attention has followed the search for cures for cancer, heart... more For decades, a great deal of public attention has followed the search for cures for cancer, heart disease and viral infections, but the single most expensive, and seemingly intractable, medical challenge in the industrialized world is Alzheimer's disease [1]. The history of Alzheimer's clinical trials has been notoriously disappointing [2], but are we truly doomed to continue repeating this futility? In fact, there are grounds for hope. In recent years, in a focal areas distinct from the clinical failures, we have seen fascinating progress on several potentially convergent fronts of that may afford promising new therapeutic opportunities.
Journal of combinatorial chemistry, Sep 29, 2010
The construction of a library of benzothiaoxazepine-1,1'-dioxides utilizing a one-pot, S N Ar div... more The construction of a library of benzothiaoxazepine-1,1'-dioxides utilizing a one-pot, S N Ar diversification-ODCT 50 scavenging protocol is reported. This protocol combines microwave irradiation to facilitate the reaction, in conjunction with a soluble ROMP-derived scavenger (ODCT) to afford the desired products in good overall purity. Utilizing this protocol, a 78-member library was successfully synthesized and submitted for biological evaluation.
Bioorganic & Medicinal Chemistry Letters, Sep 1, 2011
The first series of peptidyl aldehyde inhibitors that incorporate in their structure a glutamine ... more The first series of peptidyl aldehyde inhibitors that incorporate in their structure a glutamine surrogate has been designed and synthesized based on the known substrate specificity of Norwalk virus 3C protease. The inhibitory activity of the compounds with the protease and with a norovirus cell-based replicon system was investigated. Members of this class of compounds exhibited noteworthy activity both in vitro and in a cell-based replicon system.
Bioorganic & Medicinal Chemistry, 2013
1,2-Benzisothiazol-3(2H)-ones and 1,3,4-oxadiazoles individually have recently attracted consider... more 1,2-Benzisothiazol-3(2H)-ones and 1,3,4-oxadiazoles individually have recently attracted considerable interest in drug discovery, including as antibacterial and antifungal agents. In this study, a series of functionalized 1,2-benzisothiazol-3(2H)-one-1,3,4-oxadiazole hybrid derivatives were synthesized and subsequently screened against Dengue and West Nile virus proteases. Ten out of twenty-four compounds showed greater than 50% inhibition against DENV2 and WNV proteases ([I] = 10 μM). The IC 50 values of compound 7n against DENV2 and WNV NS2B/NS3 were found to be 3.75 ± 0.06 and 4.22 ± 0.07 μM, respectively. The kinetics data support a competitive mode of inhibition by compound 7n. Molecular modeling studies were performed to delineate the putative binding mode of this series of compounds. This study reveals that the hybrid series arising from the linking of the two scaffolds provides a suitable platform for conducting a hit-to-lead optimization campaign via iterative structure-activity relationship studies, in vitro screening and X-ray crystallography.
European journal of medicinal chemistry, 2018
Acute nonbacterial gastroenteritis caused by noroviruses constitutes a global public health conce... more Acute nonbacterial gastroenteritis caused by noroviruses constitutes a global public health concern and a significant economic burden. There are currently no small molecule therapeutics or vaccines for the treatment of norovirus infections. A structure-guided approach was utilized in the design of a series of inhibitors of norovirus 3CL protease that embody an oxazolidinone ring as a novel design element for attaining optimal binding interactions. Low micromolar cell-permeable inhibitors that display anti-norovirus activity have been identified. The mechanism of action, mode of binding, and structural rearrangements associated with the interaction of the inhibitors and the enzyme were elucidated using X-ray crystallography.
Comparative Modeling of Proteins
Springer eBooks, Sep 3, 2014
Much of the biochemistry that underlies health, medicine, and numerous biotechnology applications... more Much of the biochemistry that underlies health, medicine, and numerous biotechnology applications is regulated by proteins, whereby the ability of proteins to effect such processes is dictated by the three-dimensional structural assembly of the proteins. Thus, a detailed understanding of biochemistry requires not only knowledge of the constituent sequence of proteins, but also a detailed understanding of how that sequence folds spatially. Three-dimensional analysis of protein structures is thus proving to be a critical mode of biological and medical discovery in the early twenty-first century, providing fundamental insight into function that produces useful biochemistry and dysfunction that leads to disease. The large number of distinct proteins precludes rigorous laboratory characterization of the complete structural proteome, but fortunately efficient in silico structure prediction is possible for many proteins that have not been experimentally characterized. One technique that continues to provide accurate and efficient protein structure predictions, called comparative modeling, has become a critical tool in many biological disciplines. The discussion herein is an updated version of a previous 2008 treatise focusing on the general philosophy of comparative modeling methods and on specific strategies for successfully achieving reliable and accurate models. The chapter discusses basic aspects of template selection, sequence alignment, spatial alignment, loop and gap modeling, side chain modeling, structural refinement and validation, and provides an important new discussion on automated computational tools for protein structure prediction.
Sphingosine-1 phosphate (S1P) receptor 1 (S1PR) is one of the receptors responsible for initiatin... more Sphingosine-1 phosphate (S1P) receptor 1 (S1PR) is one of the receptors responsible for initiating intracellular signal transduction in response to extracellular signals encoded in Sphingosine-1 phosphate (S1P) and other related agonists. Using microsecond molecular dynamics simulation, rotameric (χ2) changes in the aromatic amino acids lining ligand-binding pocket, inter-helical electrostatic interaction, interaction between ligands (S1P and ML056) and selected extracellular regions of S1P have been studied. The data presented here strongly suggested that S1P-bound S1PR structure became active based on NPxxYmotif rmsd and dissociation of TM3/TM6 ionic lock as early as 300 ns while the apo-and ML056-bound S1PR were trapped in semi-active and inactive states respectively. Tyrosine 29 evolved agonist-dependent rotameric distribution while tryptophan 117 (W3.25), phenylalanine 210 (F5.47), tryptophan 269 (W6.48) and phenylalanine 273 (F6.52) exhibited activation-type signatures. Furthermore, while activation promoted TM1/TM4, TM2/TM7 and TM4/TM6 engagement, prior electrostatic engagements in TM3/TM4, TM3/TM6 and TM3/TM7 were dissolved. N-terminal-heptahelical bundle interaction is also compromised in inactive S1PR possibly due to reduced engagement of N-terminal residue such as lysine 34 and lysine 46. Ultimately, S1PR activation by class I agonist followed classical GPCR activation paradigm.
European journal of medicinal chemistry, Feb 1, 2017
Norovirus infections have a major impact on public health worldwide, yet there is a current deart... more Norovirus infections have a major impact on public health worldwide, yet there is a current dearth of norovirus-specific therapeutics and prophylactics. This report describes the discovery of a novel class of macrocyclic inhibitors of norovirus 3C-like protease, a cysteine protease that is essential for virus replication. SAR, structural, and biochemical studies were carried out to ascertain the effect of structure on pharmacological activity and permeability. Insights gained from these studies have laid a solid foundation for capitalizing on the therapeutic potential of the series of inhibitors described herein.
ACS Combinatorial Science, Apr 4, 2013
The solution-phase parallel synthesis of a diverse 71 member library of multi-substituted cyclic ... more The solution-phase parallel synthesis of a diverse 71 member library of multi-substituted cyclic imidates is described. The key intermediates, 3-iodomethylene-containing cyclic imidates, are readily prepared in good to excellent yields by the palladium/copper-catalyzed cross-coupling of various o-iodobenzamides and terminal alkynes, followed by electrophilic cyclization with I 2. These cyclic imidates were further functionalized by palladium-catalyzed Suzuki-Miyaura, Sonogashira, carbonylative amidation and Heck chemistry using sublibraries of commercially available building blocks.
Antibiotics, Dec 31, 2022
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Biochemical Pharmacology, Aug 1, 2011
HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific re... more HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.
MANT nucleotides as probes for analysis of Edema Factor, a bacterial Adenylyl Cyclase toxin
The FASEB Journal, 2007
BioTech
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
BioTech
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
BENTHAM SCIENCE PUBLISHERS eBooks, Mar 29, 2012
Ab initio Calculations of G-tensors
ChemInform, Oct 4, 2005
Skip to Main Content. ...
Glyphosate insensitive G96A mutant EPSP synthase liganded with shikimate-3-phosphate
Solution-Phase Parallel Synthesis of a Library of Δ2-Pyrazolines
ChemInform, Jun 12, 2007
ABSTRACT
Comparative Modeling of Proteins
Methods in molecular biology, 2008
Three-dimensional analysis of protein structures is proving to be one of the most fruitful modes ... more Three-dimensional analysis of protein structures is proving to be one of the most fruitful modes of biological and medical discovery in the early 21st century, providing fundamental insight into many (perhaps most) biochemical functions of relevance to the cause and treatment of diseases. Fully realizing such insight, however, would require analysis of too many distinct proteins for thorough laboratory analysis of all proteins to be feasible, thus, any method capable of accurate, efficient in silico structure prediction should prove highly expeditious. The technique generally acknowledged to provide the most accurate protein structure predictions, called comparative modeling, has, thus, attracted substantial attention and is the focus of this chapter. Although other reviews have reported on the method development and research history of comparative modeling, our discussion herein focuses on the general philosophy of the method and specific strategies for successfully achieving reliable and accurate models. The chapter, thus, relates aspects of template selection, sequence alignment, spatial alignment, loop and gap modeling, side chain modeling, structural refinement, and validation.
Synthesis of Diverse Library of 1,2-Dihydroisoquinolines Based on a Lewis Organocatalyst-Cocatalyzed Multicomponent Reaction of 2-(1-Alkynyl)Benzaldehydes, Amines and Ketones
For decades, a great deal of public attention has followed the search for cures for cancer, heart... more For decades, a great deal of public attention has followed the search for cures for cancer, heart disease and viral infections, but the single most expensive, and seemingly intractable, medical challenge in the industrialized world is Alzheimer's disease [1]. The history of Alzheimer's clinical trials has been notoriously disappointing [2], but are we truly doomed to continue repeating this futility? In fact, there are grounds for hope. In recent years, in a focal areas distinct from the clinical failures, we have seen fascinating progress on several potentially convergent fronts of that may afford promising new therapeutic opportunities.
Journal of combinatorial chemistry, Sep 29, 2010
The construction of a library of benzothiaoxazepine-1,1'-dioxides utilizing a one-pot, S N Ar div... more The construction of a library of benzothiaoxazepine-1,1'-dioxides utilizing a one-pot, S N Ar diversification-ODCT 50 scavenging protocol is reported. This protocol combines microwave irradiation to facilitate the reaction, in conjunction with a soluble ROMP-derived scavenger (ODCT) to afford the desired products in good overall purity. Utilizing this protocol, a 78-member library was successfully synthesized and submitted for biological evaluation.
Bioorganic & Medicinal Chemistry Letters, Sep 1, 2011
The first series of peptidyl aldehyde inhibitors that incorporate in their structure a glutamine ... more The first series of peptidyl aldehyde inhibitors that incorporate in their structure a glutamine surrogate has been designed and synthesized based on the known substrate specificity of Norwalk virus 3C protease. The inhibitory activity of the compounds with the protease and with a norovirus cell-based replicon system was investigated. Members of this class of compounds exhibited noteworthy activity both in vitro and in a cell-based replicon system.
Bioorganic & Medicinal Chemistry, 2013
1,2-Benzisothiazol-3(2H)-ones and 1,3,4-oxadiazoles individually have recently attracted consider... more 1,2-Benzisothiazol-3(2H)-ones and 1,3,4-oxadiazoles individually have recently attracted considerable interest in drug discovery, including as antibacterial and antifungal agents. In this study, a series of functionalized 1,2-benzisothiazol-3(2H)-one-1,3,4-oxadiazole hybrid derivatives were synthesized and subsequently screened against Dengue and West Nile virus proteases. Ten out of twenty-four compounds showed greater than 50% inhibition against DENV2 and WNV proteases ([I] = 10 μM). The IC 50 values of compound 7n against DENV2 and WNV NS2B/NS3 were found to be 3.75 ± 0.06 and 4.22 ± 0.07 μM, respectively. The kinetics data support a competitive mode of inhibition by compound 7n. Molecular modeling studies were performed to delineate the putative binding mode of this series of compounds. This study reveals that the hybrid series arising from the linking of the two scaffolds provides a suitable platform for conducting a hit-to-lead optimization campaign via iterative structure-activity relationship studies, in vitro screening and X-ray crystallography.
European journal of medicinal chemistry, 2018
Acute nonbacterial gastroenteritis caused by noroviruses constitutes a global public health conce... more Acute nonbacterial gastroenteritis caused by noroviruses constitutes a global public health concern and a significant economic burden. There are currently no small molecule therapeutics or vaccines for the treatment of norovirus infections. A structure-guided approach was utilized in the design of a series of inhibitors of norovirus 3CL protease that embody an oxazolidinone ring as a novel design element for attaining optimal binding interactions. Low micromolar cell-permeable inhibitors that display anti-norovirus activity have been identified. The mechanism of action, mode of binding, and structural rearrangements associated with the interaction of the inhibitors and the enzyme were elucidated using X-ray crystallography.
Comparative Modeling of Proteins
Springer eBooks, Sep 3, 2014
Much of the biochemistry that underlies health, medicine, and numerous biotechnology applications... more Much of the biochemistry that underlies health, medicine, and numerous biotechnology applications is regulated by proteins, whereby the ability of proteins to effect such processes is dictated by the three-dimensional structural assembly of the proteins. Thus, a detailed understanding of biochemistry requires not only knowledge of the constituent sequence of proteins, but also a detailed understanding of how that sequence folds spatially. Three-dimensional analysis of protein structures is thus proving to be a critical mode of biological and medical discovery in the early twenty-first century, providing fundamental insight into function that produces useful biochemistry and dysfunction that leads to disease. The large number of distinct proteins precludes rigorous laboratory characterization of the complete structural proteome, but fortunately efficient in silico structure prediction is possible for many proteins that have not been experimentally characterized. One technique that continues to provide accurate and efficient protein structure predictions, called comparative modeling, has become a critical tool in many biological disciplines. The discussion herein is an updated version of a previous 2008 treatise focusing on the general philosophy of comparative modeling methods and on specific strategies for successfully achieving reliable and accurate models. The chapter discusses basic aspects of template selection, sequence alignment, spatial alignment, loop and gap modeling, side chain modeling, structural refinement and validation, and provides an important new discussion on automated computational tools for protein structure prediction.
Sphingosine-1 phosphate (S1P) receptor 1 (S1PR) is one of the receptors responsible for initiatin... more Sphingosine-1 phosphate (S1P) receptor 1 (S1PR) is one of the receptors responsible for initiating intracellular signal transduction in response to extracellular signals encoded in Sphingosine-1 phosphate (S1P) and other related agonists. Using microsecond molecular dynamics simulation, rotameric (χ2) changes in the aromatic amino acids lining ligand-binding pocket, inter-helical electrostatic interaction, interaction between ligands (S1P and ML056) and selected extracellular regions of S1P have been studied. The data presented here strongly suggested that S1P-bound S1PR structure became active based on NPxxYmotif rmsd and dissociation of TM3/TM6 ionic lock as early as 300 ns while the apo-and ML056-bound S1PR were trapped in semi-active and inactive states respectively. Tyrosine 29 evolved agonist-dependent rotameric distribution while tryptophan 117 (W3.25), phenylalanine 210 (F5.47), tryptophan 269 (W6.48) and phenylalanine 273 (F6.52) exhibited activation-type signatures. Furthermore, while activation promoted TM1/TM4, TM2/TM7 and TM4/TM6 engagement, prior electrostatic engagements in TM3/TM4, TM3/TM6 and TM3/TM7 were dissolved. N-terminal-heptahelical bundle interaction is also compromised in inactive S1PR possibly due to reduced engagement of N-terminal residue such as lysine 34 and lysine 46. Ultimately, S1PR activation by class I agonist followed classical GPCR activation paradigm.
European journal of medicinal chemistry, Feb 1, 2017
Norovirus infections have a major impact on public health worldwide, yet there is a current deart... more Norovirus infections have a major impact on public health worldwide, yet there is a current dearth of norovirus-specific therapeutics and prophylactics. This report describes the discovery of a novel class of macrocyclic inhibitors of norovirus 3C-like protease, a cysteine protease that is essential for virus replication. SAR, structural, and biochemical studies were carried out to ascertain the effect of structure on pharmacological activity and permeability. Insights gained from these studies have laid a solid foundation for capitalizing on the therapeutic potential of the series of inhibitors described herein.
ACS Combinatorial Science, Apr 4, 2013
The solution-phase parallel synthesis of a diverse 71 member library of multi-substituted cyclic ... more The solution-phase parallel synthesis of a diverse 71 member library of multi-substituted cyclic imidates is described. The key intermediates, 3-iodomethylene-containing cyclic imidates, are readily prepared in good to excellent yields by the palladium/copper-catalyzed cross-coupling of various o-iodobenzamides and terminal alkynes, followed by electrophilic cyclization with I 2. These cyclic imidates were further functionalized by palladium-catalyzed Suzuki-Miyaura, Sonogashira, carbonylative amidation and Heck chemistry using sublibraries of commercially available building blocks.
Antibiotics, Dec 31, 2022
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
Biochemical Pharmacology, Aug 1, 2011
HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific re... more HAL is a multidisciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.
MANT nucleotides as probes for analysis of Edema Factor, a bacterial Adenylyl Cyclase toxin
The FASEB Journal, 2007
BioTech
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
BioTech
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
BENTHAM SCIENCE PUBLISHERS eBooks, Mar 29, 2012
Ab initio Calculations of G-tensors
ChemInform, Oct 4, 2005
Skip to Main Content. ...
Glyphosate insensitive G96A mutant EPSP synthase liganded with shikimate-3-phosphate
Solution-Phase Parallel Synthesis of a Library of Δ2-Pyrazolines
ChemInform, Jun 12, 2007
ABSTRACT