Search results for " DOCKING"
showing 10 items of 226 documents
Molecular interaction of artemisinin with translationally controlled tumor protein (TCTP) of Plasmodium falciparum
2012
Malaria causes millions of death cases per year. Since Plasmodium falciparum rapidly develops drug resistance, it is of high importance to investigate potential drug targets which may lead to novel rational therapy approaches. Here we report on the interaction of translationally controlled tumor protein of P. falciparum (PfTCTP) with the anti-malarial drug artemisinin. Furthermore, we investigated the crystal structure of PfTCTP. Using mass spectrometry, bioinformatic approaches and surface plasmon resonance spectroscopy, we identified novel binding sites of artemisinin which are in direct neighborhood to amino acids 19-46, 108-134 and 140-163. The regions covered by these residues are know…
Synthesis and Structure-Activity Relationships of Amino Acid Conjugates of Cholanic Acid as Antagonists of the EphA2 Receptor
2013
The Eph–ephrin system plays a critical role in tumor growth and vascular functions during carcinogenesis. We had previously identified cholanic acid as a competitive and reversible EphA2 antagonist able to disrupt EphA2-ephrinA1 interaction and to inhibit EphA2 activation in prostate cancer cells. Herein, we report the synthesis and biological evaluation of a set of cholanic acid derivatives obtained by conjugation of its carboxyl group with a panel of naturally occurring amino acids with the aim to improve EphA2 receptor inhibition. Structure-activity relationships indicate that conjugation of cholanic acid with linear amino acids of small size leads to effective EphA2 antagonists whereas …
Antimicrobial Activity, in silico Molecular Docking, ADMET and DFT Analysis of Secondary Metabolites from Roots of Three Ethiopian Medicinal Plants
2021
Mathewos Anza,1 Milkyas Endale,1 Luz Cardona,2 Diego Cortes,3 Rajalakshmanan Eswaramoorthy,1 Jesus Zueco,4 Hortensia Rico,4 Maria Trelis,5 Belen Abarca2 1Department of Applied Chemistry, School of Applied Natural Science, Adama Science and Technology University, Adama, Ethiopia; 2Department of Organic Chemistry, Faculty of Chemistry, University of Valencia, Burjassot, Spain; 3Department of Pharmacology, Faculty of Pharmacy, University of Valencia, Burjassot, Spain; 4Department of Microbiology and Ecology, Faculty of Pharmacy, University of Valencia, Burjassot, Spain; 5Parasites and Health Research Group, Department of Pharmacy, Pharmaceutical Technology and Parasitology, Faculty of Pharmacy…
Design of antitumor drugs targeting c-kit receptor by a new mixed ligand-structure based method
2020
An important challenge, in the medicinal chemistry field, is the research of novel forceful drugs to overcome tumor-acquired resistance. The c-Kit tyrosine kinase receptor (TKR) represents a suitable target for the carcinogenesis control of gastro-intestinal stromal (GIST), leukemia, and mastocytosis tumors; nevertheless, several hotspot mutations of the protein limit the efficacy of a few clinical administered TKRs inhibitors. In this study, a new in silico protocol based on ligand and structure-based combined method is proposed, with the aim to identify a set of new c-Kit inhibitors able to complex c-Kit mutated proteins. A recent and freely available web-server DRUDIT is used for the lig…
Experimental-Like Affinity Constants and Enantioselectivity Estimates from Flexible Docking
2012
Experimental-like affinity constants and enantioselectivity estimates, not predicted so far computationally, were obtained using a novel flexible modeling/docking combined strategy. The S- and R-warfarin-human serum albumin (HSA, site I) complexes were used as an interaction model. The process for a verified estimation includes the following: (i) ionized open chain forming at physiological pH (a recent focus); (ii) conformational search (molecular mechanics and Monte Carlo methods); (iii) rigid protein-flexible ligand docking (GlideXP) generating low energy paired S- and R-poses; (iv) graphical comparison against the X-ray crystal structure (unsatisfactory verification step); (v) quantum po…
Exploring the SARS-CoV-2 Proteome in the Search of Potential Inhibitors via Structure-based Pharmacophore Modeling/Docking Approach
2020
To date, SARS-CoV-2 infectious disease, named COVID-19 by the World Health Organization (WHO) in February 2020, has caused millions of infections and hundreds of thousands of deaths. Despite the scientific community efforts, there are currently no approved therapies for treating this coronavirus infection. The process of new drug development is expensive and time-consuming, so that drug repurposing may be the ideal solution to fight the pandemic. In this paper, we selected the proteins encoded by SARS-CoV-2 and using homology modeling we identified the high-quality model of proteins. A structure-based pharmacophore modeling study was performed to identify the pharmacophore features for each…
Design, Synthesis and Biological Evaluation of 7-Chloro-9
2019
Glycogen synthase kinase-3β (GSK-3β) represents a relevant drug target for the treatment of neurodegenerative pathologies including Alzheimer’s disease. We herein report on the optimization of a novel class of GSK-3β inhibitors based on the tofacitinib-derived screen hit 3-((3R,4R)-3-((7-chloro-9H-pyrimido[4,5-b]indol-4-yl)(methyl)amino)-4-methylpiperidin-1-yl)-3-oxopropanenitrile (1). We synthesized a series of 19 novel 7-chloro-9H-pyrimido[4,5-b]indole-based derivatives and studied their structure–activity relationships with focus on the cyanoacetyl piperidine moiety. We unveiled the crucial role of the nitrile group and its importance for the activity of this compound series. A successfu…
Molecular docking and oxidation kinetics of 3-phenyl coumarin derivatives by human CYP2A13.
2021
CYP2A13 enzyme is expressed in human extrahepatic tissues, while CYP2A6 is a hepatic enzyme. Reactions catalysed by CYP2A13 activate tobacco-specific nitrosamines and some other toxic xenobiotics in lungs.To compare oxidation characteristics and substrate-enzyme active site interactions in CYP2A13 vs CYP2A6, we evaluated CYP2A13 mediated oxidation characteristics of 23 coumarin derivatives and modelled their interactions at the enzyme active site.CYP2A13 did not oxidise six coumarin derivatives to corresponding fluorescent 7-hydroxycoumarins. The Km-values of the other coumarins varied 0.85-97 µM, Vmax-values of the oxidation reaction varied 0.25-60 min-1, and intrinsic clearance varied 26-…
Cytotoxicity of the bisphenolic honokiol from Magnolia officinalis against multiple drug-resistant tumor cells as determined by pharmacogenomics and …
2014
A main problem in oncology is the development of drug-resistance. Some plant-derived lignans are established in cancer therapy, e.g. the semisynthetic epipodophyllotoxins etoposide and teniposide. Their activity is, unfortunately, hampered by the ATP-binding cassette (ABC) efflux transporter, P-glycoprotein. Here, we investigated the bisphenolic honokiol derived from Magnolia officinalis. P-glycoprotein-overexpressing CEM/ADR5000 cells were not cross-resistant to honokiol, but MDA-MB-231 BRCP cells transfected with another ABC-transporter, BCRP, revealed 3-fold resistance. Further drug resistance mechanisms analyzed study was the tumor suppressor TP53 and the epidermal growth factor recepto…