The Experts below are selected from a list of 13896 Experts worldwide ranked by ideXlab platform
Seth M. Cohen - One of the best experts on this subject based on the ideXlab platform.
-
the effect of metalloprotein inhibitors on cellular metal ion content and distribution
Metallomics, 2017Co-Authors: Barry Lai, Yao Chen, Zhenjie Zhang, Seth M. CohenAbstract:With Metalloproteins garnering increased interest as therapeutic targets, designing target-specific metalloprotein inhibitors (MPi) is of substantial importance. However, in many respects, the development and evaluation of MPi lags behind that of conventional small molecule therapeutics. Core concerns around MPi, such as target selectivity and potential disruption of metal ion homeostasis linger. Herein, we used a suite of analytical methods, including energy-dispersive X-ray spectroscopy (EDX), inductively coupled plasma atomic emission spectroscopy (ICP-OES), and synchrotron X-ray fluorescence microscopy (SXRF) to investigate the effect of several MPi on cellular metal ion distribution and homeostasis. The results reveal that at therapeutically relevant concentrations, the tested MPi have no significant effects on cellular metal ion content or distribution. In addition, the affinity of the metal-binding pharmacophore (MBP) utilized by the MPi does not have a substantial influence on the effect of the MPi on cellular metal distribution. These studies provide an important, original data set indicating that metal ion homeostasis is not notably perturbed by MPi, which should encourage the development of and aid in designing new MPi, guide MBP selection, and clarify the effect of MPi on the ‘metallome’.
-
Investigating the Selectivity of Metalloenzyme Inhibitors in the Presence of Competing Metalloproteins.
ChemMedChem, 2015Co-Authors: Yao Chen, Seth M. CohenAbstract:Metalloprotein inhibitors (MPi) are an important class of therapeutics for the treatment of a variety of diseases, including hypertension, cancer, and HIV/AIDS. However, despite their clinical success, there is an apprehension that MPi may be less selective than other small-molecule therapeutics and more prone to inhibit off-target metalloenzymes. We examined the issue of MPi specificity by investigating the selectivity of a variety of MPi against a representative panel of metalloenzymes in the presence of competing Metalloproteins (metallothionein, myoglobin, carbonic anhydrase, and transferrin). Our findings reveal that a wide variety of MPi do not exhibit a decrease in inhibitory activity in the presence of large excesses of competing Metalloproteins, suggesting that the competing proteins do not titrate the MPi away from its intended target. This study represents a rudimentary but important means to mimic the biological milieu, which contains other Metalloproteins that could compete the MPi away from its target. The strategy used in this study may be a useful approach to examine the selectivity of other MPi in development.
-
Metalloprotein-Inhibitor Binding: Human Carbonic Anhydrase II as a Model for Probing Metal-Ligand Interactions in a Metalloprotein Active Site.
Inorganic Chemistry, 2013Co-Authors: David P. Martin, Zachary S. Hann, Seth M. CohenAbstract:An ever-increasing number of Metalloproteins are being discovered that play essential roles in physiological processes. Inhibitors of these proteins have significant potential for the treatment of human disease, but clinical success of these compounds has been limited. Herein, zinc(II)-dependent metalloprotein inhibitors in clinical use are reviewed, and the potential for using novel metal-binding groups (MBGs) in the design of these inhibitors is discussed. By using human carbonic anhydrase II as a model system, the nuances of MBG–metal interactions in the context of a protein environment can be probed. Understanding how metal coordination influences inhibitor binding may help in the design of new therapeutics targeting Metalloproteins.
-
Emerging trends in metalloprotein inhibition
Dalton Transactions, 2011Co-Authors: Matthieu Rouffet, Seth M. CohenAbstract:Numerous Metalloproteins are important therapeutic targets that are gaining increased attention in the medicinal and bioinorganic chemistry communities. This Perspective article describes some emerging trends and recent findings in the area of metalloprotein inhibitor discovery and development. In particular, increasing recognition of the importance of the metal–ligand interactions in these systems calls for more input and consideration from the bioinorganic community to address questions traditionally confined to the medicinal chemistry community.
-
The design of inhibitors for medicinally relevant Metalloproteins.
ChemMedChem, 2007Co-Authors: Faith E. Jacobsen, Jana A. Lewis, Seth M. CohenAbstract:A number of Metalloproteins are important medicinal targets for conditions ranging from pathogenic infections to cancer. Many but not all of these Metalloproteins contain a zinc(II) ion in the protein active site. Small-molecule inhibitors of these Metalloproteins are designed to bind directly to the active site metal ions. In this review several Metalloproteins of interest are discussed, including matrix metalloproteinases (MMPs), histone deacetylases (HDACs), anthrax lethal factor (LF), and others. Different strategies that have been employed to design effective inhibitors against these proteins are described, with an effort to highlight the strengths and drawbacks of each approach. An emphasis is placed on examining the bioinorganic chemistry of these metal active sites and how a better understanding of the coordination chemistry in these systems may lead to improved inhibitors. It is hoped that this review will help inspire medicinal, biological, and inorganic chemists to tackle this important problem by considering all aspects of metalloprotein inhibitor design.
Xicheng Wang - One of the best experts on this subject based on the ideXlab platform.
-
an accurate metalloprotein specific scoring function and molecular docking program devised by a dynamic sampling and iteration optimization strategy
Journal of Chemical Information and Modeling, 2015Co-Authors: Sha Liao, Junfeng Gu, Hualiang Jiang, Xicheng Wang, Honglin LiAbstract:Metalloproteins, particularly zinc Metalloproteins, are promising therapeutic targets, and recent efforts have focused on the identification of potent and selective inhibitors of these proteins. However, the ability of current drug discovery and design technologies, such as molecular docking and molecular dynamics simulations, to probe metal–ligand interactions remains limited because of their complicated coordination geometries and rough treatment in current force fields. Herein we introduce a robust, multiobjective optimization algorithm-driven metalloprotein-specific docking program named MpSDock, which runs on a scheme similar to consensus scoring consisting of a force-field-based scoring function and a knowledge-based scoring function. For this purpose, in this study, an effective knowledge-based zinc metalloprotein-specific scoring function based on the inverse Boltzmann law was designed and optimized using a dynamic sampling and iteration optimization strategy. This optimization strategy can dynami...
-
an accurate metalloprotein specific scoring function and molecular docking program devised by a dynamic sampling and iteration optimization strategy
Journal of Chemical Information and Modeling, 2015Co-Authors: Sha Liao, Hualiang Jiang, Fang Bai, Xicheng WangAbstract:Metalloproteins, particularly zinc Metalloproteins, are promising therapeutic targets, and recent efforts have focused on the identification of potent and selective inhibitors of these proteins. However, the ability of current drug discovery and design technologies, such as molecular docking and molecular dynamics simulations, to probe metal-ligand interactions remains limited because of their complicated coordination geometries and rough treatment in current force fields. Herein we introduce a robust, multiobjective optimization algorithm-driven metalloprotein-specific docking program named MpSDock, which runs on a scheme similar to consensus scoring consisting of a force-field-based scoring function and a knowledge-based scoring function. For this purpose, in this study, an effective knowledge-based zinc metalloprotein-specific scoring function based on the inverse Boltzmann law was designed and optimized using a dynamic sampling and iteration optimization strategy. This optimization strategy can dynamically sample and regenerate decoy poses used in each iteration step of refining the scoring function, thus dramatically improving both the effectiveness of the exploration of the binding conformational space and the sensitivity of the ranking of the native binding poses. To validate the zinc metalloprotein-specific scoring function and its special built-in docking program, denoted MpSDockZn, an extensive comparison was performed against six universal, popular docking programs: Glide XP mode, Glide SP mode, Gold, AutoDock, AutoDock4Zn, and EADock DSS. The zinc metalloprotein-specific knowledge-based scoring function exhibited prominent performance in accurately describing the geometries and interactions of the coordination bonds between the zinc ions and chelating agents of the ligands. In addition, MpSDockZn had a competitive ability to sample and identify native binding poses with a higher success rate than the other six docking programs.
Fang Bai - One of the best experts on this subject based on the ideXlab platform.
-
an accurate metalloprotein specific scoring function and molecular docking program devised by a dynamic sampling and iteration optimization strategy
Journal of Chemical Information and Modeling, 2015Co-Authors: Sha Liao, Hualiang Jiang, Fang Bai, Xicheng WangAbstract:Metalloproteins, particularly zinc Metalloproteins, are promising therapeutic targets, and recent efforts have focused on the identification of potent and selective inhibitors of these proteins. However, the ability of current drug discovery and design technologies, such as molecular docking and molecular dynamics simulations, to probe metal-ligand interactions remains limited because of their complicated coordination geometries and rough treatment in current force fields. Herein we introduce a robust, multiobjective optimization algorithm-driven metalloprotein-specific docking program named MpSDock, which runs on a scheme similar to consensus scoring consisting of a force-field-based scoring function and a knowledge-based scoring function. For this purpose, in this study, an effective knowledge-based zinc metalloprotein-specific scoring function based on the inverse Boltzmann law was designed and optimized using a dynamic sampling and iteration optimization strategy. This optimization strategy can dynamically sample and regenerate decoy poses used in each iteration step of refining the scoring function, thus dramatically improving both the effectiveness of the exploration of the binding conformational space and the sensitivity of the ranking of the native binding poses. To validate the zinc metalloprotein-specific scoring function and its special built-in docking program, denoted MpSDockZn, an extensive comparison was performed against six universal, popular docking programs: Glide XP mode, Glide SP mode, Gold, AutoDock, AutoDock4Zn, and EADock DSS. The zinc metalloprotein-specific knowledge-based scoring function exhibited prominent performance in accurately describing the geometries and interactions of the coordination bonds between the zinc ions and chelating agents of the ligands. In addition, MpSDockZn had a competitive ability to sample and identify native binding poses with a higher success rate than the other six docking programs.
Sha Liao - One of the best experts on this subject based on the ideXlab platform.
-
an accurate metalloprotein specific scoring function and molecular docking program devised by a dynamic sampling and iteration optimization strategy
Journal of Chemical Information and Modeling, 2015Co-Authors: Sha Liao, Junfeng Gu, Hualiang Jiang, Xicheng Wang, Honglin LiAbstract:Metalloproteins, particularly zinc Metalloproteins, are promising therapeutic targets, and recent efforts have focused on the identification of potent and selective inhibitors of these proteins. However, the ability of current drug discovery and design technologies, such as molecular docking and molecular dynamics simulations, to probe metal–ligand interactions remains limited because of their complicated coordination geometries and rough treatment in current force fields. Herein we introduce a robust, multiobjective optimization algorithm-driven metalloprotein-specific docking program named MpSDock, which runs on a scheme similar to consensus scoring consisting of a force-field-based scoring function and a knowledge-based scoring function. For this purpose, in this study, an effective knowledge-based zinc metalloprotein-specific scoring function based on the inverse Boltzmann law was designed and optimized using a dynamic sampling and iteration optimization strategy. This optimization strategy can dynami...
-
an accurate metalloprotein specific scoring function and molecular docking program devised by a dynamic sampling and iteration optimization strategy
Journal of Chemical Information and Modeling, 2015Co-Authors: Sha Liao, Hualiang Jiang, Fang Bai, Xicheng WangAbstract:Metalloproteins, particularly zinc Metalloproteins, are promising therapeutic targets, and recent efforts have focused on the identification of potent and selective inhibitors of these proteins. However, the ability of current drug discovery and design technologies, such as molecular docking and molecular dynamics simulations, to probe metal-ligand interactions remains limited because of their complicated coordination geometries and rough treatment in current force fields. Herein we introduce a robust, multiobjective optimization algorithm-driven metalloprotein-specific docking program named MpSDock, which runs on a scheme similar to consensus scoring consisting of a force-field-based scoring function and a knowledge-based scoring function. For this purpose, in this study, an effective knowledge-based zinc metalloprotein-specific scoring function based on the inverse Boltzmann law was designed and optimized using a dynamic sampling and iteration optimization strategy. This optimization strategy can dynamically sample and regenerate decoy poses used in each iteration step of refining the scoring function, thus dramatically improving both the effectiveness of the exploration of the binding conformational space and the sensitivity of the ranking of the native binding poses. To validate the zinc metalloprotein-specific scoring function and its special built-in docking program, denoted MpSDockZn, an extensive comparison was performed against six universal, popular docking programs: Glide XP mode, Glide SP mode, Gold, AutoDock, AutoDock4Zn, and EADock DSS. The zinc metalloprotein-specific knowledge-based scoring function exhibited prominent performance in accurately describing the geometries and interactions of the coordination bonds between the zinc ions and chelating agents of the ligands. In addition, MpSDockZn had a competitive ability to sample and identify native binding poses with a higher success rate than the other six docking programs.
Richard Ortega - One of the best experts on this subject based on the ideXlab platform.
-
Synchrotron radiation for direct analysis of Metalloproteins on electrophoresis gels
Metallomics, 2009Co-Authors: Richard OrtegaAbstract:Metalloproteomics requires analytical techniques able to assess and quantify the inorganic species in Metalloproteins. The most widely used methods are hyphenated techniques, based on the coupling of a high resolution chromatographic method with a high sensitivity method for metal analysis in solution. An alternative approach is the use of methods for solid sample analysis, combining metalloprotein separation by gel electrophoresis and direct analysis of the gels. Direct methods are based on beam analysis, such as lasers, ion beams or synchrotron radiation beams. The aim of this review article is to present the main features of synchrotron radiation based methods and their applications for metalloprotein analysis directly on electrophoresis gels. Synchrotron radiation X-ray fluorescence has been successfully employed for sensitive metal identification, and X-ray absorption spectroscopy for metal local structure speciation in proteins. Synchrotron based methods will be compared to ion beam and mass spectrometry for direct analysis of Metalloproteins in electrophoresis gels.
