Erybraedin C, a natural compound from the plant Bituminaria bituminosa, inhibits both the cleavage and religation activities of human topoisomerase I

2010 ◽  
Vol 425 (3) ◽  
pp. 531-539 ◽  
Author(s):  
Cinzia Tesauro ◽  
Paola Fiorani ◽  
Ilda D'Annessa ◽  
Giovanni Chillemi ◽  
Gino Turchi ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Topoisomerase I ◽  
Natural Compound ◽  
Antitumour Activity ◽  
Enzyme Reaction ◽  
Drug Binding ◽  
Active Site Residues ◽  
Docking Simulations ◽  
Drug Binding Site ◽  
Bituminaria Bituminosa

The interaction of human topoisomerase I and erybraedin C, a pterocarpan purified from the plant Bituminaria bituminosa, that was shown to have an antitumour activity, was investigated through enzymatic activity assays and molecular docking procedures. Erybraedin C is able to inhibit both the cleavage and the religation steps of the enzyme reaction. In both cases, pre-incubation of the drug with the enzyme is required to produce a complete inhibition. Molecular docking simulations indicate that, when interacting with the enzyme alone, the preferential drug-binding site is localized in proximity to the active Tyr723 residue, with one of the two prenilic groups close to the active-site residues Arg488 and His632, essential for the catalytic reaction. When interacting with the cleavable complex, erybraedin C interacts with both the enzyme and DNA in a way similar to that found for topotecan. This is the first example of a natural compound able to act on both the cleavage and religation reaction of human topoisomerase I.

scholarly journals µ-Theraphotoxin-Pn3a inhibition of Cav3.3 channels reveals a novel isoform-selective drug binding site

2021 ◽  
Author(s):  
Jeffrey R. McArthur ◽  
Jierong Wen ◽  
Andrew Hung ◽  
Rocio K. Finol-Urdaneta ◽  
David J. Adams
Keyword(s):  
Low Voltage ◽  
Therapeutic Potential ◽  
Cardiac Pace ◽  
Drug Binding ◽  
Calcium Currents ◽  
Computational Docking ◽  
Docking Simulations ◽  
Drug Binding Site ◽  
Preferential Binding ◽  
Subtype Selective

Low voltage-activated calcium currents are mediated by T-type calcium channels CaV3.1, CaV3.2, and CaV3.3, which modulate a variety of physiological processes including sleep, cardiac pace-making, pain, and epilepsy. CaV3 isoforms’ biophysical properties, overlapping expression and lack of subtype-selective pharmacology hinder the determination of their specific physiological roles in health and disease. Notably, CaV3.3’s contribution to normal and pathophysiological function has remained largely unexplored. We have identified Pn3a as the first subtype-selective spider venom peptide inhibitor of CaV3.3, with >100-fold lower potency against the other T-type isoforms. Pn3a modifies CaV3.3 gating through a depolarizing shift in the voltage dependence of activation thus decreasing CaV3.3-mediated currents in the normal range of activation potentials. Paddle chimeras of KV1.7 channels bearing voltage sensor sequences from all four CaV3.3 domains revealed preferential binding of Pn3a to the S3-S4 region of domain II (CaV3.3DII). This novel T-type channel pharmacological site was explored through computational docking simulations of Pn3a into all T-type channel isoforms highlighting it as subtype-specific pharmacophore with therapeutic potential. This research expands our understanding of T-type calcium channel pharmacology and supports the suitability of Pn3a as a molecular tool in the study of the physiological roles of CaV3.3 channels.

scholarly journals Drug-binding energetics of human α-1-acid glycoprotein assessed by isothermal titration calorimetry and molecular docking simulations

2012 ◽  
Vol 25 (12) ◽  
pp. 642-656 ◽  
Author(s):  
Johnny X. Huang ◽  
Matthew A. Cooper ◽  
Mark A. Baker ◽  
Mohammad A. K. Azad ◽  
Roger L. Nation ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Isothermal Titration Calorimetry ◽  
Drug Binding ◽  
Titration Calorimetry ◽  
Docking Simulations ◽  
Acid Glycoprotein ◽  
Binding Energetics

Drug Repurposing Studies Targeting SARS-nCoV2: An Ensemble Docking Approach on Drug Target 3C-like Protease (3CLpro)

2020 ◽  
Author(s):  
Shruti Koulgi ◽  
Vinod Jani ◽  
Mallikarjunachari Uppuladinne ◽  
Uddhavesh Sonavane ◽  
Asheet Kumar Nath ◽  
...  
Keyword(s):  
Drug Repurposing ◽  
Drug Binding ◽  
Ensemble Docking ◽  
Drug Molecules ◽  
Drug Binding Site ◽  
Main Protease ◽  
Docking Approach ◽  
Novel Coronavirus ◽  
Markov State Modeling ◽  
Viral Polyprotein

<p>The COVID-19 pandemic has been responsible for several deaths worldwide. The causative agent behind this disease is the Severe Acute Respiratory Syndrome – novel Coronavirus 2 (SARS-nCoV2). SARS-nCoV2 belongs to the category of RNA viruses. The main protease, responsible for the cleavage of the viral polyprotein is considered as one of the hot targets for treating COVID-19. Earlier reports suggest the use of HIV anti-viral drugs for targeting the main protease of SARS-CoV, which caused SARS in the year 2002-03. Hence, drug repurposing approach may prove to be useful in targeting the main protease of SARS-nCoV2. The high-resolution crystal structure of 3CL<sup>pro</sup> (main protease) of SARS-nCoV2 (PDB ID: 6LU7) was used as the target. The Food and Drug Administration (FDA) approved and SWEETLEAD database of drug molecules were screened. The apo form of the main protease was simulated for a cumulative of 150 ns and 10 μs open source simulation data was used, to obtain conformations for ensemble docking. The representative structures for docking were selected using RMSD-based clustering and Markov State Modeling analysis. This ensemble docking approach for main protease helped in exploring the conformational variation in the drug binding site of the main protease leading to efficient binding of more relevant drug molecules. The drugs obtained as best hits from the ensemble docking possessed anti-bacterial and anti-viral properties. Small molecules with these properties may prove to be useful to treat symptoms exhibited in COVID-19. This <i>in-silico</i> ensemble docking approach would support identification of potential candidates for repurposing against COVID-19.</p>

In Silico Approach to Inhibition of Tyrosinase by Ascorbic Acid Using Molecular Docking Simulations

2014 ◽  
Vol 14 (12) ◽  
pp. 1469-1472 ◽  
Author(s):  
F. Senol ◽  
M. Khan ◽  
Gurdal Orhan ◽  
Erdem Gurkas ◽  
Ilkay Orhan ◽  
...  
Keyword(s):  
Ascorbic Acid ◽  
Molecular Docking ◽  
In Silico ◽  
Docking Simulations

Interactions of Non-Phosphorous Glycerolipids with DNA: Energetics, Molecular Docking and Topoisomerase I Attenuation

2016 ◽  
Vol 16 (3) ◽  
pp. 335-346
Author(s):  
Valery Y. Grinberg ◽  
Vladimir B. Tsvetkov ◽  
Alina A. Markova ◽  
Lyubov G. Dezhenkova ◽  
Tatiana V. Burova ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Topoisomerase I

scholarly journals Discovery of novel potential KIT inhibitors for the treatment of gastrointestinal stromal tumor

2021 ◽  
Vol 16 (1) ◽  
pp. 303-310
Author(s):  
Lili Jiang ◽  
Zhongmin Zhang ◽  
Zhen Wang ◽  
Yong Liu
Keyword(s):  
Molecular Docking ◽  
Gastrointestinal Stromal Tumor ◽  
Pharmacophore Modeling ◽  
Stromal Tumor ◽  
Strong Hydrogen Bond ◽  
Ligand Complex ◽  
Hydrogen Bond Interaction ◽  
Mutant Proteins ◽  
Docking Simulations ◽  
Pharmacophore Models

Abstract Numerous inhibitors of tyrosine-protein kinase KIT, a receptor tyrosine kinase, have been explored as a viable therapy for the treatment of gastrointestinal stromal tumor (GIST). However, drug resistance due to acquired mutations in KIT makes these drugs almost useless. The present study was designed to screen the novel inhibitors against the activity of the KIT mutants through pharmacophore modeling and molecular docking. The best two pharmacophore models were established using the KIT mutants’ crystal complexes and were used to screen the new compounds with possible KIT inhibitory activity against both activation loop and ATP-binding mutants. As a result, two compounds were identified as potential candidates from the virtual screening, which satisfied the potential binding capabilities, molecular modeling characteristics, and predicted absorption, distribution, metabolism, excretion, toxicity (ADMET) properties. Further molecular docking simulations showed that two compounds made strong hydrogen bond interaction with different KIT mutant proteins. Our results indicated that pharmacophore models based on the receptor–ligand complex had excellent ability to screen KIT inhibitors, and two compounds may have the potential to develop further as the future KIT inhibitors for GIST treatment.

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