scholarly journals Traditional Phytochemistry: Identification of Drug by ‘Taste’

2007 ◽  
Vol 4 (2) ◽  
pp. 145-148 ◽  
Author(s):  
Kalpana Joshi ◽  
Alex Hankey ◽  
Bhushan Patwardhan
Keyword(s):  
Traditional Medicine ◽  
Active Site ◽  
Active Sites ◽  
The Body ◽  
Pharmacological Properties ◽  
Specific Enzyme ◽  
Materia Medica ◽  
Enzyme Active Site ◽  
Scientific Approach ◽  
Hypo Thesis

Ayurveda, the system of traditional medicine from India, holds that ‘Rasa’, a concept roughly corresponding to taste, is a basis for identifying pharmacological properties of plants and other materia medica used in Dravyaguna—its system of phytomedicine. This idea has recently found support in studies of ibuprofen, the pharmacological properties of which are similar to those of oleocanthal, because the two substances have very similar tastes. This paper discusses a possible scientific approach to understanding the Ayurvedic (hypo)thesis in terms of the stereochemical basis of both pharamaco-activity and taste, and the numbers of possible pharmaco-active compounds that ‘Rasa’ may be able to distinguish. We conclude that molecules binding to a specific enzyme active site should have their own ‘Rasa’, and that the number of different subjectively experienced ‘tastes’ is more than enough to distinguish between molecular shapes binding to all enzyme active sites in the body.

Structures of human cytosolic and mitochondrial nucleotidases: implications for structure-based design of selective inhibitors

2014 ◽  
Vol 70 (2) ◽  
pp. 461-470 ◽  
Author(s):  
Petr Pachl ◽  
Milan Fábry ◽  
Ivan Rosenberg ◽  
Ondřej Šimák ◽  
Pavlína Řezáčová ◽  
...  
Keyword(s):  
Active Site ◽  
Active Sites ◽  
Specific Inhibitor ◽  
Detailed Comparison ◽  
Atomic Resolution ◽  
Phosphate Anion ◽  
Protonation State ◽  
Interatomic Distances ◽  
Enzyme Active Site ◽  
Resolution Structure

The human 5′(3′)-deoxyribonucleotidases catalyze the dephosphorylation of deoxyribonucleoside monophosphates to the corresponding deoxyribonucleosides and thus help to maintain the balance between pools of nucleosides and nucleotides. Here, the structures of human cytosolic deoxyribonucleotidase (cdN) at atomic resolution (1.08 Å) and mitochondrial deoxyribonucleotidase (mdN) at near-atomic resolution (1.4 Å) are reported. The attainment of an atomic resolution structure allowed interatomic distances to be used to assess the probable protonation state of the phosphate anion and the side chains in the enzyme active site. A detailed comparison of the cdN and mdN active sites allowed the design of a cdN-specific inhibitor.

scholarly journals Phytochemistry and therapeutic effects of Alhagi spp. and tarangabin in the Traditional and modern medicine: a review

2020 ◽  
Vol 9 (2) ◽  
pp. 86-104
Author(s):  
Amir Parviz Tavassoli ◽  
Majid Anushiravani ◽  
Seyed Mousalreza Hoseini ◽  
Zahra Nikakhtar ◽  
Hamideh Naghedi Baghdar ◽  
...  
Keyword(s):  
Clinical Research ◽  
Traditional Medicine ◽  
Geographical Distribution ◽  
Modern Medicine ◽  
Therapeutic Effects ◽  
Pharmacological Properties ◽  
Medicinal Uses ◽  
Materia Medica ◽  
Medicinal Properties ◽  
Different Parts

Alhagi maurorum is one of the species of Alhagi genus producing manna of Tarangabin. Tarangabin is mainly prepared in Iran and Afghanistan. The medicinal properties of Tarangabin and A. maurorum have been mentioned in some major Materia Medica manuscripts in the Islamic era. Tarangabin has various pharmacological properties including antioxidant, anti-inflammatory, antipyretic, diaphoretic, diuretic, expectorant, analgesic and gastrointestinal effects. The purpose of this review is to introduce Alhagi plant and its different species, to present its geographical distribution, and to review its phytochemical and pharmacological properties as well as traditional and folklore applications. Phytochemistry of different parts of Alhagi, such as root, leaf and manna is also explained in details. In addition, temperament and medicinal uses of Tarangabin mentioned in the Islamic traditional medicine (ITM) books are presented. Indeed, sparse clinical research has been done on the medicinal properties of Tarangabin, which calls for future well-designed trials.

scholarly journals Ultrafast infrared spectroscopy reveals water-mediated coherent dynamics in an enzyme active site

2015 ◽  
Vol 6 (1) ◽  
pp. 505-516 ◽  
Author(s):  
Katrin Adamczyk ◽  
Niall Simpson ◽  
Gregory M. Greetham ◽  
Andrea Gumiero ◽  
Martin A. Walsh ◽  
...  
Keyword(s):  
Infrared Spectroscopy ◽  
Active Site ◽  
Active Sites ◽  
Dynamic Nature ◽  
Enzyme Active Site ◽  
Coherent Dynamics ◽  
Peroxidase Enzymes ◽  
Ultrafast Infrared

Ultrafast infrared spectroscopy provides insights into the dynamic nature of water in the active sites of catalase and peroxidase enzymes.

scholarly journals Assessment of enzyme active site positioning and tests of catalytic mechanisms through X-ray–derived conformational ensembles

2020 ◽  
Vol 117 (52) ◽  
pp. 33204-33215
Author(s):  
Filip Yabukarski ◽  
Justin T. Biel ◽  
Margaux M. Pinney ◽  
Tzanko Doukov ◽  
Alexander S. Powers ◽  
...  
Keyword(s):  
Active Site ◽  
Active Sites ◽  
Enzyme Design ◽  
Reaction Cycle ◽  
New Era ◽  
X Ray ◽  
Enzyme Active Site ◽  
Conformational Ensembles ◽  
X Ray Crystallography ◽  
General Base

How enzymes achieve their enormous rate enhancements remains a central question in biology, and our understanding to date has impacted drug development, influenced enzyme design, and deepened our appreciation of evolutionary processes. While enzymes position catalytic and reactant groups in active sites, physics requires that atoms undergo constant motion. Numerous proposals have invoked positioning or motions as central for enzyme function, but a scarcity of experimental data has limited our understanding of positioning and motion, their relative importance, and their changes through the enzyme’s reaction cycle. To examine positioning and motions and test catalytic proposals, we collected “room temperature” X-ray crystallography data for Pseudomonas putida ketosteroid isomerase (KSI), and we obtained conformational ensembles for this and a homologous KSI from multiple PDB crystal structures. Ensemble analyses indicated limited change through KSI’s reaction cycle. Active site positioning was on the 1- to 1.5-Å scale, and was not exceptional compared to noncatalytic groups. The KSI ensembles provided evidence against catalytic proposals invoking oxyanion hole geometric discrimination between the ground state and transition state or highly precise general base positioning. Instead, increasing or decreasing positioning of KSI’s general base reduced catalysis, suggesting optimized Ångstrom-scale conformational heterogeneity that allows KSI to efficiently catalyze multiple reaction steps. Ensemble analyses of surrounding groups for WT and mutant KSIs provided insights into the forces and interactions that allow and limit active-site motions. Most generally, this ensemble perspective extends traditional structure–function relationships, providing the basis for a new era of “ensemble–function” interrogation of enzymes.

scholarly journals Structure ofStaphylococcus aureusadenylosuccinate lyase (PurB) and assessment of its potential as a target for structure-based inhibitor discovery

2010 ◽  
Vol 66 (8) ◽  
pp. 881-888 ◽  
Author(s):  
Paul K. Fyfe ◽  
Alice Dawson ◽  
Marie-Theres Hutchison ◽  
Scott Cameron ◽  
William N. Hunter
Keyword(s):  
Active Site ◽  
Active Sites ◽  
Bacterial Pathogen ◽  
Enzyme Mechanism ◽  
Enzyme Active Site ◽  
Adenylosuccinate Lyase ◽  
Medium Resolution ◽  
Inhibitor Discovery ◽  
Species Specific ◽  
Distinct Subunit

The medium-resolution structure of adenylosuccinate lyase (PurB) from the bacterial pathogenStaphylococcus aureusin complex with AMP is presented. Oxalate, which is likely to be an artifact of crystallization, has been modelled in the active site and occupies a position close to that where succinate is observed in orthologous structures. PurB catalyzes reactions that support the provision of purines and the control of AMP/fumarate levels. As such, the enzyme is predicted to be essential for the survival ofS. aureusand to be a potential therapeutic target. Comparisons of this pathogen PurB with the enzyme fromEscherichia coliare presented to allow discussion concerning the enzyme mechanism. Comparisons with human PurB suggest that the close similarity of the active sites would make it difficult to identify species-specific inhibitors for this enyme. However, there are differences in the way that the subunits are assembled into dimers. The distinct subunit–subunit interfaces may provide a potential area to target by exploiting the observation that creation of the enzyme active site is dependent on oligomerization.

scholarly journals Assessment of enzyme active site positioning and tests of catalytic mechanisms through X-ray-derived conformational ensembles

2019 ◽  
Author(s):  
Filip Yabukarski ◽  
Justin T Biel ◽  
Margaux M Pinney ◽  
Tzanko Doukov ◽  
Alexander S Powers ◽  
...  
Keyword(s):  
Active Site ◽  
Active Sites ◽  
Enzyme Design ◽  
Reaction Cycle ◽  
New Era ◽  
X Ray ◽  
Enzyme Active Site ◽  
Conformational Ensembles ◽  
X Ray Crystallography ◽  
General Base

AbstractHow enzymes achieve their enormous rate enhancements remains a central question in biology, and our understanding to date has impacted drug development, influenced enzyme design, and deepened our appreciation of evolutionary processes. While enzymes position catalytic and reactant groups in active sites, physics requires that atoms undergo constant motion. Numerous proposals have invoked positioning or motions as central for enzyme function, but a scarcity of experimental data has limited our understanding of positioning and motion, their relative importance, and their changes through the enzyme’s reaction cycle. To examine positioning and motions and test catalytic proposals, we collected “room temperature” X-ray crystallography data for P. putida ketosteroid isomerase (KSI), and we obtained conformational ensembles for this and a homologous KSI from multiple PDB crystal structures. Ensemble analyses indicated limited change through KSI’s reaction cycle. Active site positioning was on the 1-1.5 Å scale, and was not exceptional compared to non-catalytic groups. The KSI ensembles provided evidence against catalytic proposals invoking oxyanion hole geometric discrimination between the ground state and transition state or highly precise general base positioning. Instead, increasing or decreasing positioning of KSI’s general base reduced catalysis, suggesting optimized Ångstrom-scale conformational heterogeneity that allows KSI to efficiently catalyze multiple reaction steps. Ensemble analyses of surrounding groups for WT and mutant KSIs provided insights into the forces and interactions that allow and limit active site motions. Most generally, this ensemble perspective extends traditional structure–function relationships, providing the basis for a new era of “ensemble–function” interrogation of enzymes.

Catalytic Resonance Theory: Parallel Reaction Pathway Control

2019 ◽  
Author(s):  
M. Alexander Ardagh ◽  
Manish Shetty ◽  
Anatoliy Kuznetsov ◽  
Qi Zhang ◽  
Phillip Christopher ◽  
...  
Keyword(s):  
Chemical Reactions ◽  
Active Site ◽  
Active Sites ◽  
Reaction Pathway ◽  
Control Strategies ◽  
Oscillation Amplitude ◽  
Catalytic Performance ◽  
Parallel Reaction ◽  
Resonance Theory ◽  
Static Conditions

Catalytic enhancement of chemical reactions via heterogeneous materials occurs through stabilization of transition states at designed active sites, but dramatically greater rate acceleration on that same active site is achieved when the surface intermediates oscillate in binding energy. The applied oscillation amplitude and frequency can accelerate reactions orders of magnitude above the catalytic rates of static systems, provided the active site dynamics are tuned to the natural frequencies of the surface chemistry. In this work, differences in the characteristics of parallel reactions are exploited via selective application of active site dynamics (0 < ΔU < 1.0 eV amplitude, 10<sup>-6</sup> < f < 10<sup>4</sup> Hz frequency) to control the extent of competing reactions occurring on the shared catalytic surface. Simulation of multiple parallel reaction systems with broad range of variation in chemical parameters revealed that parallel chemistries are highly tunable in selectivity between either pure product, even when specific products are not selectively produced under static conditions. Two mechanisms leading to dynamic selectivity control were identified: (i) surface thermodynamic control of one product species under strong binding conditions, or (ii) catalytic resonance of the kinetics of one reaction over the other. These dynamic parallel pathway control strategies applied to a host of chemical conditions indicate significant potential for improving the catalytic performance of many important industrial chemical reactions beyond their existing static performance.

scholarly journals Conformation-Specific Inhibitory Anti-MMP-7 Monoclonal Antibody Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Chemotherapeutic Cell Kill

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1679
Author(s):  
Vishnu Mohan ◽  
Jean P. Gaffney ◽  
Inna Solomonov ◽  
Maxim Levin ◽  
Mordehay Klepfish ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Active Site ◽  
Drug Targets ◽  
Fas Ligand ◽  
Specific Activity ◽  
Matrix Metalloproteases ◽  
Ductal Adenocarcinoma ◽  
Enzyme Active Site ◽  
Induced Apoptosis

Matrix metalloproteases (MMPs) undergo post-translational modifications including pro-domain shedding. The activated forms of these enzymes are effective drug targets, but generating potent biological inhibitors against them remains challenging. We report the generation of anti-MMP-7 inhibitory monoclonal antibody (GSM-192), using an alternating immunization strategy with an active site mimicry antigen and the activated enzyme. Our protocol yielded highly selective anti-MMP-7 monoclonal antibody, which specifically inhibits MMP-7′s enzyme activity with high affinity (IC50 = 132 ± 10 nM). The atomic model of the MMP-7-GSM-192 Fab complex exhibited antibody binding to unique epitopes at the rim of the enzyme active site, sterically preventing entry of substrates into the catalytic cleft. In human PDAC biopsies, tissue staining with GSM-192 showed characteristic spatial distribution of activated MMP-7. Treatment with GSM-192 in vitro induced apoptosis via stabilization of cell surface Fas ligand and retarded cell migration. Co-treatment with GSM-192 and chemotherapeutics, gemcitabine and oxaliplatin elicited a synergistic effect. Our data illustrate the advantage of precisely targeting catalytic MMP-7 mediated disease specific activity.

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