scholarly journals Mechanism-based enzyme activating compounds

2020 ◽  
Author(s):  
Xiangying Guan ◽  
Alok Upadhyay ◽  
Raj Chakrabarti
Keyword(s):  
Steady State ◽  
Small Molecule ◽  
Active Sites ◽  
Degrees Of Freedom ◽  
Enzymatic Catalysis ◽  
Enzyme Activation ◽  
Allosteric Site ◽  
Age Related ◽  
Small Molecule Modulators ◽  
Enzyme Activators

Compared to inhibitors, which constitute the vast majority of today’s drugs, enzyme activators have considerable advantages, especially in the context of enzymes that regulate reactive flux through metabolic pathways associated with chronic, age-related diseases and lifespan. Across all families of enzymes, only a dozen or so distinct classes of small molecule activators have been characterized. Enzyme activators that are not based on naturally evolved allosteric mechanisms are much more difficult to design than inhibitors, because enzymatic catalysis has been optimized over billions of years of evolution. Here, we introduce modes of enzyme activation based on the catalytic reaction mechanisms of enzymes for which naturally evolved activators may not exist. We establish biophysical properties of small molecule modulators that are necessary to achieve desired changes in the steady state and non-steady state parameters of these enzymes, including changes in local conformational degrees of freedom conducive to the enhancement of catalytic activity that can be identified through computational modeling of their active sites. We illustrate how the modes of action of several compounds reported to activate enzymes without known allosteric sites may be understood using the framework presented. We also present simulations and new experimental results in support of this framework, including identification of the mechanism of a compound that activates the human SIRT3 enzyme, which does not contain a known allosteric site, under physiologically relevant conditions.

Nonallosteric Sirtuin Enzyme Activation: Characterization of Hit Compounds

2020 ◽  
Author(s):  
A Upadhyay ◽  
X Guan ◽  
S Munshi ◽  
R Chakrabarti
Keyword(s):  
Degrees Of Freedom ◽  
Enzyme Activation ◽  
Dynamics Simulation ◽  
Ligand Docking ◽  
Multiple Substrates ◽  
Physiological Importance ◽  
Age Related ◽  
Dependent Protein ◽  
Catalyzed Reactions ◽  
Small Molecule Modulators

ABSTRACTMammalian sirtuins (SIRT1-SIRT7) are a family of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacylases that play critical roles in lifespan and age-related diseases. The physiological importance of sirtuins has stimulated intense interest in designing sirtuin-activating compounds. However, except for allosteric activators of SIRT1-catalyzed reactions that are limited to particular substrates, a general framework for the design of sirtuin-activating compounds has been lacking. Recently, we introduced a general mode of sirtuin activation that is distinct from the known modes of enzyme activation, establishing biophysical properties of small molecule modulators that can, in principle, result in enzyme activation for various sirtuins and substrates. Here, we characterize small molecules reported in the literature to activate the SIRT3 enzyme using a variety of computational, biochemical and biophysical techniques including protein-ligand docking, molecular dynamics simulation, nonlinear reaction dynamics simulation, kinetic assays and thermodynamic assays with multiple substrates and protocols. In particular, we identify the mechanism of action of the compound honokiol on the human SIRT3 enzyme, modeling its effect on active site conformational degrees of freedom and demonstrating how it nonallosterically activates the human SIRT3 enzyme under physiologically relevant conditions. We show that honokiol constitutes a hit compound for the design of a new generation of nonallosteric activators that can activate SIRT3 through the proposed mechanism-based mode of activation.

scholarly journals Mechanism-based sirtuin enzyme activation

2015 ◽  
Author(s):  
Xiangying Guan ◽  
Alok Upadhyay ◽  
Sudipto Munshi ◽  
Raj Chakrabarti
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
False Positives ◽  
Enzyme Activation ◽  
Label Free ◽  
Multiple Substrates ◽  
Dependent Protein ◽  
Biophysical Techniques ◽  
Catalyzed Reactions ◽  
Small Molecule Modulators

AbstractSirtuin enzymes are NAD+-dependent protein deacylases that play a central role in the regulation of healthspan and lifespan in organisms ranging from yeast to mammals. There is intense interest in the activation of the seven mammalian sirtuins (SIRT1-7) in order to extend mammalian healthspan and lifespan. However, there is currently no understanding of how to design sirtuin-activating compounds beyond allosteric activators of SIRT1-catalyzed reactions that are limited to particular substrates. Moreover, across all families of enzymes, only a dozen or so distinct classes of non-natural small molecule activators have been characterized, with only four known modes of activation among them. None of these modes of activation are based on the unique catalytic reaction mechanisms of the target enzymes. Here, we report a general mode of sirtuin activation that is distinct from the known modes of enzyme activation. Based on the conserved mechanism of sirtuin-catalyzed deacylation reactions, we establish biophysical properties of small molecule modulators that can in principle result in enzyme activation for diverse sirtuins and substrates. Building upon this framework, we propose strategies for the identification, characterization and evolution of hits for mechanism-based enzyme activating compounds. We characterize several small molecules reported in the literature to activate sirtuins besides SIRT1, using a variety of biochemical and biophysical techniques including label-free and labeled kinetic and thermodynamic assays with multiple substrates and protocols for the identification of false positives. We provide evidence indicating that several of these small molecules reported in the published literature are false positives, and identify others as hit compounds for the design of compounds that can activate sirtuins through the proposed mechanism-based mode of action.

scholarly journals Polymer Microparticles Prolong Delivery of the 15-PGDH Inhibitor SW033291

Pharmaceutics ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 85
Author(s):  
Alan B. Dogan ◽  
Nathan A. Rohner ◽  
Julianne N. P. Smith ◽  
Jessica A. Kilgore ◽  
Noelle S. Williams ◽  
...  
Keyword(s):  
Steady State ◽  
Small Molecule ◽  
Small Molecule Drugs ◽  
Standard Clinical Practice ◽  
Age Related ◽  
Time Period ◽  
Molecule Inhibitor ◽  
Delivery Platform ◽  
Fibrotic Diseases ◽  
Polymer Microparticles

As the prevalence of age-related fibrotic diseases continues to increase, novel antifibrotic therapies are emerging to address clinical needs. However, many novel therapeutics for managing chronic fibrosis are small-molecule drugs that require frequent dosing to attain effective concentrations. Although bolus parenteral administrations have become standard clinical practice, an extended delivery platform would achieve steady-state concentrations over a longer time period with fewer administrations. This study lays the foundation for the development of a sustained release platform for the delivery of (+)SW033291, a potent, small-molecule inhibitor of the 15-hydroxyprostaglandin dehydrogenase (15-PGDH) enzyme, which has previously demonstrated efficacy in a murine model of pulmonary fibrosis. Herein, we leverage fine-tuned cyclodextrin microparticles—specifically, β-CD microparticles (β-CD MPs)—to extend the delivery of the 15-PGDH inhibitor, (+)SW033291, to over one week.

scholarly journals Polymer microparticles prolong delivery of the 15-PGDH inhibitor SW033291

2021 ◽  
Author(s):  
Alan B. Dogan ◽  
Nathan A. Rohner ◽  
Julianne N.P. Smith ◽  
Jessica A. Kilgore ◽  
Noelle S. Williams ◽  
...  
Keyword(s):  
Steady State ◽  
Small Molecule ◽  
Small Molecule Drugs ◽  
Standard Clinical Practice ◽  
Age Related ◽  
Time Period ◽  
Molecule Inhibitor ◽  
Delivery Platform ◽  
Fibrotic Diseases ◽  
Polymer Microparticles

As the prevalence of age-related fibrotic diseases continues to increase, novel antifibrotic therapies are emerging to address clinical needs. However, many novel therapeutics for managing chronic fibrosis are small-molecule drugs that require frequent dosing to attain effective concentrations. While bolus parenteral administrations have become standard clinical practice, an extended delivery platform would achieve steady state concentrations over a longer time period with fewer administrations. This study lays the foundation for the development of a sustained release platform for the delivery of (+)SW033291, a potent, small-molecule inhibitor of the 15-hydroxyprostaglandin dehydrogenase (15-PGDH) enzyme, which has previously demonstrated efficacy in a murine model of pulmonary fibrosis. Herein, we leverage fine-tuned cyclodextrin microparticles - specifically β-CD microparticles (β-CD MPs) - to extend the delivery of 15-PGDH inhibitor, (+)SW033291, to over one week.

scholarly journals Small-molecule modulators of inward rectifier K+channels: recent advances and future possibilities

2010 ◽  
Vol 2 (5) ◽  
pp. 757-774 ◽  
Author(s):  
Gautam Bhave ◽  
Daniel Lonergan ◽  
Brian A Chauder ◽  
Jerod S Denton
Keyword(s):  
Small Molecule ◽  
Inward Rectifier ◽  
K Channels ◽  
Recent Advances ◽  
Small Molecule Modulators

Beam-Vibration Analysis With the Electric-Analog Computer

1950 ◽  
Vol 17 (1) ◽  
pp. 13-26
Author(s):  
G. D. McCann ◽  
R. H. MacNeal
Keyword(s):  
Steady State ◽  
Vibration Analysis ◽  
Degrees Of Freedom ◽  
Analog Computer ◽  
Accurate Solution ◽  
Rotary Inertia ◽  
Beam Vibration ◽  
Lumped Constant ◽  
Electric Analog

Abstract The authors have developed a true dynamic analogy which has been used with the Cal Tech electric-analog computer for the rapid and accurate solution of both steady-state and transient beam problems. This analogy has been found well suited to the study of beams having several coupled degrees of freedom, including torsion, simple bending, and bending in a plane. Damping and effects such as rotary inertia may be handled readily. The analogy may also be used in the study of systems involving combined beams and “lumped-constant” elements.

Effects of Suspension Design on the Attitudes of a Car during Braking and Acceleration

1973 ◽  
Vol 187 (1) ◽  
pp. 787-794
Author(s):  
J. R. Ellis
Keyword(s):  
Steady State ◽  
Linear Systems ◽  
Degrees Of Freedom ◽  
Coupled Systems ◽  
Two Degrees Of Freedom ◽  
Simulation Techniques ◽  
Non Linear ◽  
Non Linear Systems ◽  
Effort Distribution

Two degrees of freedom models of a car are employed to demonstrate the effects of the suspension derivative ∂ x/∂ z on the pitch and bounce attitudes during braking or accelerating. The work equation is employed to show that brake effort distribution between the axles has a significant effect on the attitudes when anti-dive suspension characteristics are utilized. The steady-state positions in both pitch and bounce are developed for linear systems of typical suspensions that may be either standard or coupled systems. Non-linear systems are considered using simulation techniques. A description of some simulation circuits is contained in an appendix.

Periodic Steady State Response and Fatigue Analysis of a Nonlinear City Bus Model

2009 ◽  
Author(s):  
George Valsamos ◽  
Christos Theodosiou ◽  
Sotirios Natsiavas
Keyword(s):  
Steady State ◽  
Degrees Of Freedom ◽  
Nonlinear Models ◽  
Equations Of Motion ◽  
High Stress ◽  
Direct Determination ◽  
Accurate Information ◽  
Steady State Response ◽  
State Response ◽  
Periodic Steady State

Dynamic response related to fatigue prediction of an urban bus is investigated. First, a quite complete model subjected to road excitation is employed in order to extract sufficiently reliable and accurate information in a fast way. The bus model is set up by applying the finite element method, resulting to an excessive number of degrees of freedom. In addition, the bus suspension units involve nonlinear characterstics. A step towards alleviating this difficulty is the application of an appropriate coordinate transformation, causing a drastic reduction in the dimension of the final set of the equations of motion. This allows the application of a systematic numerical methodology leading to direct determination of periodic steady state response of nonlinear models subjected to periodic excitation. Next, typical results were obtained for excitation resulting from selected urban road profiles. These profiles have either a known form or known statistical properties, expressed by an appropriate spatial power spectral density function. In all cases examined, the emphasis was put on investigating ride response. The main attention was focused on identifying areas of the bus suspension and frame subsystems where high stress levels are developed. This information is based on the idea of a nonlinear transfer function and provides the basis for applying suitable criteria in order to perform analyses leading to prediction of fatigue failure.

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