Search results for "docking"

2021

The binding of natural ligands and synthetic drugs to the P2Y12 receptor is of great interest because of its crucial role in platelets activation and the therapy of arterial thrombosis. Up to now, all computational studies of P2Y12 concentrated on the available crystal structures, while the role of intrinsic protein dynamics and the membrane environment in the functioning of P2Y12 was not clear. In this work, we performed all-atom molecular dynamics simulations of the full-length P2Y12 receptor in three different membrane environments and in two possible conformations derived from available crystal structures. The binding of ticagrelor, its two major metabolites, adenosine diphosphate (ADP)…

Identification of a new series of amides as non-covalent proteasome inhibitors

2014

Proteasome inhibition has emerged as an important therapeutic strategy for the treatment of multiple myeloma (MM) and some forms of lymphoma, with potential application in other types of cancers. 20S proteasome consists of three different catalytic activities known as chymotrypsin-like (ChT-L), trypsin-like (T-L), and, post-glutamyl peptide hydrolyzing (PGPH) or caspase-like (C-L), which are located respectively on the β5, β2, and β1 subunits of each heptameric β rings. Currently a wide number of covalent proteasome inhibitors are reported in literature; however, the less widely investigated non-covalent inhibitors might be a promising alternative to employ in therapy, because of the lack o…

Synthesis and biological activities of a new class of heat shock protein 90 inhibitors, designed by energy-based pharmacophore virtual screening

2013

The design through energy-based pharmacophore virtual screening has led to aminocyanopyridine derivatives as efficacious new inhibitors of Hsp90. The synthesized compounds showed a good affinity for the Hsp90 ATP binding site in the competitive binding assay. Moreover, they showed an excellent antiproliferative activity against a large number of human tumor cell lines. Further biological studies on the derivative with the higher EC50 confirmed its specific influence on the cellular pathways involving Hsp90.

Synthesis, biological evaluation, and molecular docking studies of aldotetronic acid-based LpxC inhibitors

2022

: In order to develop novel inhibitors of the bacterial deacetylase LpxC bearing a substituent to target the UDP binding site of the enzyme, a series of aldotetronic acid-based hydroxamic acids was accessed in chiral pool syntheses starting from 4,6-O-benzylidene-d-glucose and l-arabinitol. The synthesized hydroxamic acids were tested for LpxC inhibitory activity in vitro, revealing benzyl ether 17a ((2S,3S)-4-(benzyloxy)-N,3-dihydroxy-2-[(4-{[4-(morpholinomethyl)phenyl]ethynyl}benzyl)oxy]butanamide) as the most potent LpxC inhibitor. This compound was additionally tested for antibacterial activity against a panel of clinically relevant Gram-negative bacteria, bacterial uptake, and suscepti…

A Novel Series of Acylhydrazones as Potential Anti-Candida Agents: Design, Synthesis, Biological Evaluation and In Silico Studies

2019

In the context of an increased incidence of invasive fungal diseases, there is an imperative need of new antifungal drugs with improved activity and safety profiles. A novel series of acylhydrazones bearing a 1,4-phenylene-bisthiazole scaffold was designed based on an analysis of structures known to possess anti-Candida activity obtained from a literature review. Nine final compounds were synthesized and evaluated in vitro for their inhibitory activity against various strains of Candida spp. The anti-Candida activity assay revealed that some of the new compounds are as active as fluconazole against most of the tested strains. A molecular docking study was conducted in order to evaluate the …

Synthesis, Properties and Antimicrobial Activity of 5-Trifluoromethyl-2-formylphenylboronic Acid

2020

2-Formylphenylboronic acids display many interesting features, not only from synthetic but also from an application as well as structural points of view. 5-Trifluoromethyl-2-formyl phenylboronic acid has been synthesized and characterized in terms of its structure and properties. The presence of an electron-withdrawing substituent results in a considerable rise in the acidity in comparison with its analogues. In some solutions, the title compound isomerizes with formation of the corresponding 3-hydroxybenzoxaborole. Taking into account the probable mechanism of antifungal action of benzoxaboroles, which blocks the cytoplasmic leucyl-tRNA synthetase (LeuRS) of the microorganism, docking stud…

Ursolic acid ameliorates stress and reactive oxygen species in C. elegans knockout mutants by the dopamine Dop1 and Dop3 receptors.

2020

Abstract Background Depression and stress-related disorders are leading causes of death worldwide. Standard treatments elevating serotonin or noradrenaline levels are not sufficiently effective and cause adverse side effects. A connection between dopamine pathways and stress-related disorders has been suggested. Compounds derived from herbal medicine could be a promising alternative. We examined the neuroprotective effects of ursolic acid (UA) by focusing on dopamine signalling. Methods Trolox equivalent capacity assay was used to determine the antioxidant activities of UA in vitro. C. elegans N2 wildtype and dopamine receptor-knockout mutants (dop-1-deficient RB665 and dop-3-deficient LX70…

The triterpenoid ursolic acid ameliorates stress in Caenorhabditis elegans by affecting the depression-associated genes skn-1 and prdx2.

2021

Abstract Introduction Depression is one of the leading causes of death worldwide. Lower antioxidant concentrations and increased oxidative stress levels contribute to the development of depression. Effective and tolerable medications are urgently needed. Nrf2 and PRDX2 are promising targets in the treatment of oxidative stress and, therefore, promising for the development of novel antidepressants. Ursolic acid (UA), a natural triterpenoid found in various plants is known to exert neuroprotective and antioxidant effects. Skn-1 (which corresponds to human Nrf2) and prdx2 deficient mutants of the nematode Caenorhabditis elegans are suitable models to study the effect of UA on these targets. Ad…

Design of new DNA-interactive agents by molecular docking and QSPR approach

2010

The design of new series of pyrrolo-pyrimidine derivatives, further annelated with a third heterocycle of different size, which also present several chain shape moieties of variable length and with different physico-chemical character, is reported. In this contribution we showed that the combination of docking-based and QSPR-based methods could lead to good models for ligand-DNA interaction prediction. By means of these computational approaches on 360 proposed inhibitors, we were able to select the most promising candidates as DNA-interactive drugs potentially endowed with antitumor activity.

The biomaterial polyphosphate blocks stoichiometric binding of the SARS-CoV-2 S-protein to the cellular ACE2 receptor

2020

The effect of the polyanionic polymer of inorganic polyphosphate (polyP) involved in innate immunity on the binding of the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein to the cellular ACE2 receptor was studied. The RBD surface comprises a basic amino acid stretch of four arginine residues which interact with the physiological polyP (polyP40) and polyP3. Subsequently, the interaction of RBD with ACE2 is sensitively inhibited. After the chemical modification of arginine, an increased inhibition by polyP, at a 1 : 1 molar ratio (polyP : RBP), is measured already at 0.1 μg mL−1. Heparin was ineffective. The results suggest a potential therapeutic benefit of polyP against SARS-C…