Developing new hybrid scaffold for urease inhibition based on carbazole-chalcone conjugates: Synthesis, assessment of therapeutic potential and computational docking analysis

2019 ◽  
Vol 27 (22) ◽  
pp. 115123 ◽  
Author(s):  
Madiha Kazmi ◽  
Imtiaz Khan ◽  
Ajmal Khan ◽  
Sobia Ahsan Halim ◽  
Aamer Saeed ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Urease Inhibition ◽  
Docking Analysis ◽  
Hybrid Scaffold ◽  
Computational Docking

Selection of oxypeucedanin as a potential antagonist from molecular docking analysis of HSP90

2020 ◽  
Vol 0 (0) ◽  
Author(s):  
Joshua Oluwasegun Bamidele ◽  
George Oche Ambrose ◽  
Oluwaseun Suleiman Alakanse
Keyword(s):  
Molecular Docking ◽  
Liver Toxicity ◽  
Docking Study ◽  
Docking Studies ◽  
Molecular Docking Study ◽  
Docking Analysis ◽  
Computational Docking ◽  
Drug Candidates ◽  
Expression Rate ◽  
Client Proteins

AbstractHSP90 is observed as one of the copious molecular chaperones that play a key role in mediating appropriate folding, maturation, and firmness of many client proteins in cells. The expression rate of HSP90 in cancer cells is at a level of 2- to 10-fold higher than the 1- to 2-fold of its unstressed and healthy ones. To combat this, several inhibitors to HSP90 protein have been studied (such as geldanamycin and its derivative 17-AAG and 17-DMAG) and have shown some primary side effects including plague, nausea, vomiting, and liver toxicity, hence the search for the best-in-class inhibitor for this protein through in silico. This study is aimed at analyzing the inhibitory potency of oxypeucedanin-a furocoumarin derivations, which have been reported to have antipoliferative activity in human prostrate carcinoma DN145 cells, and three other drug candidates retrieved from the literature via computational docking studies. The results showed oxypeucedanin as the compound with the highest binding energy of −9.2 kcal/mol. The molecular docking study was carried out using PyRx, Auto Dock Vina option, and the target was validated to confirm the proper target and the docking procedure employed for this study.

scholarly journals Bepridil is potent against SARS-CoV-2 In Vitro

2020 ◽  
Author(s):  
Erol C. Vatansever ◽  
Kai Yang ◽  
Kaci C. Kratch ◽  
Aleksandra Drelich ◽  
Chia-Chuan Cho ◽  
...  
Keyword(s):  
Small Molecule ◽  
A549 Cells ◽  
Live Virus ◽  
Docking Analysis ◽  
Computational Docking ◽  
Main Protease ◽  
Infected Cells ◽  
Endosomal Ph ◽  
Cytopathogenic Effect

ABSTRACTGuided by a computational docking analysis, about 30 FDA/EMA-approved small molecule medicines were characterized on their inhibition of the SARS-CoV-2 main protease (MPro). Of these tested small molecule medicines, six displayed an IC50 value in inhibiting MPro below 100 μM. Three medicines pimozide, ebastine, and bepridil are basic small molecules. Their uses in COVID-19 patients potentiate dual functions by both raising endosomal pH to slow SARS-CoV-2 entry into the human cell host and inhibiting MPro in infected cells. A live virus-based microneutralization assay showed that bepridil inhibited cytopathogenic effect induced by SARS-CoV-2 in Vero E6 cells completely at and dose-dependently below 5 μM and in A549 cells completely at and dose-dependently below 6.25 μM. Therefore, the current study urges serious considerations of using bepridil in COVID-19 clinical tests.

in silico Docking Analysis of Small Molecule Inhibitors from Nyctanthes arbor-tristis against Nipah Virus Infection

2019 ◽  
Vol 4 (4) ◽  
pp. 244-247
Author(s):  
Nayana Mohan ◽  
V. Meera ◽  
J. Soja ◽  
M.S. Latha
Keyword(s):  
Virus Infection ◽  
Early Stage ◽  
Nipah Virus ◽  
Docking Simulation ◽  
Severe Illness ◽  
Highly Pathogenic ◽  
Docking Analysis ◽  
Computational Docking ◽  
In Silico Docking ◽  
Biosafety Level

Nipah virus is a highly pathogenic paramyxovirus belonging to the genus Henipavirus, classified as Biosafety Level 4 (BSL4) agents. The virus causes severe illness characterized by encephalitis or respiratory disease in human. The case-lethality rate of Nipah was reported to be 70 % in India, since year 2001. Despite the high pathogenicity of virus, no therapeutics are currently approved for use in human. But, ribavirin, favipiravir and human mono clonal antibody was found to reduce the intensity in early stage. Medicinal plants serve as a rich source of therapeutically active compounds. Nyctanthus arbortristis Linn or pavizhamalli (Harsinger) is traditionally known to have activity against Nipha virus. In this study, therapeutic activity of phytochemicals arbortristoside A and arbortristoside C present in pavizhamalli plant against Nipha virus target was investigated by computational docking simulation. Computational docking analysis was performed using Schrodinger Suite. The phytochemicals arbortristoside A and arbortristoside C show promising binding affinity with the target Nipah virus than the reference drugs. Results of the study could be advantageous to develop a new lead molecule against Nipah virus infection.

scholarly journals Geometric Simulation Approach for Grading and Assessing the Thermostability of CALBs

2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
B. Senthilkumar ◽  
D. Meshachpaul ◽  
R. Rajasekaran
Keyword(s):  
Surface Area ◽  
Structural Parameters ◽  
Conformational Sampling ◽  
Docking Analysis ◽  
Computational Docking ◽  
Highly Active ◽  
Structural Rigidity ◽  
Biodiesel Synthesis ◽  
The Stability ◽  
Thermostable Lipases

Candida antarcticalipase B (CALB) is a known stable and highly active enzyme used widely in biodiesel synthesis. In this work, the stability of native (4K6G) and mutant (4K5Q) CALB was studied through various structural parameters using conformational sampling approach. The contours of polar surface area and surface area of mutant CALB were 11357.67 Å2and 30007.4 Å2, respectively, showing an enhanced stability compared to native CALB with a statistically significantPvalue of < 0.0001. Moreover, simulated thermal denaturation of CALB, a process involving dilution of hydrogen bond, significantly shielded against different intervals of energy application in mutant CALB revealing its augmentation of structural rigidity against native CALB. Finally, computational docking analysis showed an increase in the binding affinity of CALB and its substrate (triglyceride) in mutant CALB with Atomic Contact Energy (ACE) of −91.23 kcal/mol compared to native CALB (ACE of −70.3 kcal/mol). The computational observations proposed that the use of mutant CALB (4K5Q) could serve as a best template for production of biodiesel in the future. Additionally, it can also be used as a template to identify efficient thermostable lipases through further mutations.

scholarly journals Bepridil is potent against SARS-CoV-2 in vitro

2021 ◽  
Vol 118 (10) ◽  
pp. e2012201118 ◽  
Author(s):  
Erol C. Vatansever ◽  
Kai S. Yang ◽  
Aleksandra K. Drelich ◽  
Kaci C. Kratch ◽  
Chia-Chuan Cho ◽  
...  
Keyword(s):  
European Medicines Agency ◽  
Dependent Manner ◽  
Live Virus ◽  
Docking Analysis ◽  
Computational Docking ◽  
Main Protease ◽  
Infected Cells ◽  
Endosomal Ph ◽  
Dose Dependent

Guided by a computational docking analysis, about 30 Food and Drug Administration/European Medicines Agency (FDA/EMA)-approved small-molecule medicines were characterized on their inhibition of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro). Of these small molecules tested, six displayed a concentration that inhibits response by 50% (IC50) value below 100 μM in inhibiting Mpro, and, importantly, three, that is, pimozide, ebastine, and bepridil, are basic molecules that potentiate dual functions by both raising endosomal pH to interfere with SARS-CoV-2 entry into the human cell host and inhibiting Mpro in infected cells. A live virus-based modified microneutralization assay revealed that bepridil possesses significant anti−SARS-CoV-2 activity in both Vero E6 and A459/ACE2 cells in a dose-dependent manner with low micromolar effective concentration, 50% (EC50) values. Therefore, the current study urges serious considerations of using bepridil in COVID-19 clinical tests.

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 Elevated ABCB1 Expression Confers Acquired Resistance to Aurora Kinase Inhibitor GSK-1070916 in Cancer Cells

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhuo-Xun Wu ◽  
Yuqi Yang ◽  
Jing-Quan Wang ◽  
Wen-Min Zhou ◽  
Junyu Chen ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Clinical Investigation ◽  
Acquired Resistance ◽  
Aurora Kinase ◽  
Aurora Kinase Inhibitor ◽  
Anticancer Effect ◽  
Docking Analysis ◽  
Computational Docking ◽  
Abcb1 Transporter ◽  
High Binding Affinity

The emergence of multidrug resistance (MDR) has been a major issue for effective cancer chemotherapy as well as targeted therapy. One prominent factor that causes MDR is the overexpression of ABCB1 transporter. In the present study, we revealed that the Aurora kinase inhibitor GSK-1070916 is a substrate of ABCB1. GSK-1070916 is a newly developed inhibitor that is currently under clinical investigation. The cytotoxicity assay showed that overexpression of ABCB1 significantly hindered the anticancer effect of GSK-1070916 and the drug resistance can be abolished by the addition of an ABCB1 inhibitor. GSK-1070916 concentration-dependently stimulated ABCB1 ATPase activity. The HPLC drug accumulation assay suggested that the ABCB1-overexpressing cells had lower levels of intracellular GSK-1070916 compared with the parental cells. GSK-1070916 also showed high binding affinity to ABCB1 substrate-binding site in the computational docking analysis. In conclusion, our study provides strong evidence that ABCB1 can confer resistance to GSK-1070916, which should be taken into consideration in clinical setting.

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