scholarly journals Analogs of TIQ-A as inhibitors of human mono-ADP-ribosylating PARPs

2021 ◽  
Author(s):  
Mirko M Maksimainen ◽  
Sudarshan Murthy ◽  
Sven T Sowa ◽  
Albert Galera-Prat ◽  
Elena Rolina ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Structural Changes ◽  
Binding Modes ◽  
Activity Profiling ◽  
Adp Ribosyltransferase ◽  
Complex Crystal

The scaffold of TIQ-A, a previously known inhibitor of human poly-ADP-ribosyltransferase PARP1, was utilized to develop inhibitors against human mono-ADP-ribosyltransferases through structure-guided design and activity profiling. By supplementing the TIQ-A scaffold with small structural changes, based on a PARP10 inhibitor OUL35, selectivity changed from poly-ADP-ribosyltransferases towards mono-ADP-ribosyltransferases. Binding modes of analogs were experimentally verified by determining complex crystal structures with mono-ADP-ribosyltransferase PARP15 and with poly-ADP-ribosyltransferase TNKS2. The best analogs of the study achieved 10-20-fold selectivity towards mono-ADP-ribosyltransferases PARP10 and PARP15 while maintaining micromolar potencies. The work demonstrates a route to differentiate compound selectivity between mono- and poly-ribosyltransferases of the human ARTD family.

scholarly journals Multi-Targeting Bioactive Compounds Extracted from Essential Oils as Kinase Inhibitors

Molecules ◽  
2020 ◽  
Vol 25 (9) ◽  
pp. 2174 ◽  
Author(s):  
Annalisa Maruca ◽  
Delia Lanzillotta ◽  
Roberta Rocca ◽  
Antonio Lupia ◽  
Giosuè Costa ◽  
...  
Keyword(s):  
Essential Oils ◽  
Binding Affinity ◽  
Structural Changes ◽  
Kinase Inhibitors ◽  
Synergistic Effects ◽  
Data Bank ◽  
Binding Modes ◽  
Starting Point ◽  
Target Action ◽  
Potential Resource

Essential oils (EOs) are popular in aromatherapy, a branch of alternative medicine that claims their curative effects. Moreover, several studies reported EOs as potential anti-cancer agents by inducing apoptosis in different cancer cell models. In this study, we have considered EOs as a potential resource of new kinase inhibitors with a polypharmacological profile. On the other hand, computational methods offer the possibility to predict the theoretical activity profile of ligands, discovering dangerous off-targets and/or synergistic effects due to the potential multi-target action. With this aim, we performed a Structure-Based Virtual Screening (SBVS) against X-ray models of several protein kinases selected from the Protein Data Bank (PDB) by using a chemoinformatics database of EOs. By evaluating theoretical binding affinity, 13 molecules were detected among EOs as new potential kinase inhibitors with a multi-target profile. The two compounds with higher percentages in the EOs were studied more in depth by means Induced Fit Docking (IFD) protocol, in order to better predict their binding modes taking into account also structural changes in the receptor. Finally, given its good binding affinity towards five different kinases, cinnamyl cinnamate was biologically tested on different cell lines with the aim to verify the antiproliferative activity. Thus, this work represents a starting point for the optimization of the most promising EOs structure as kinase inhibitors with multi-target features.

scholarly journals Thiophene-containing thiolato dimers, oxygen inserted Cu(II) complex, crystal structures, molecular docking and theoretical studies

2016 ◽  
Vol 69 (11-13) ◽  
pp. 2015-2023 ◽  
Author(s):  
Shaikh M. Mobin ◽  
Mohd. Tauqeer ◽  
Akbar Mohammad ◽  
Veenu Mishra ◽  
Pratibha Kumari
Keyword(s):  
Molecular Docking ◽  
Crystal Structures ◽  
Theoretical Studies ◽  
Complex Crystal

scholarly journals Plasmodium falciparum DHODH inhibitor complexes reveal flexible binding site

2014 ◽  
Vol 70 (a1) ◽  
pp. C1793-C1793
Author(s):  
Paul Rowland ◽  
Onkar SINGH ◽  
Leila Ross ◽  
Francisco Gamo ◽  
Maria Lafuente-Monasterio ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Binding Site ◽  
Crystal Structures ◽  
Point Mutations ◽  
Crystal Form ◽  
Drug Binding ◽  
Binding Modes ◽  
Resistance Mutations ◽  
Drug Binding Site

Malaria is a preventable and treatable disease, yet annually there are still hundreds of thousands of malaria-related deaths. The disease is caused by infection with mosquito-borne Plasmodium parasites. With hundreds of millions of cases each year there is a very high potential for drug resistance and this has compromised many existing therapies. One target under investigation is the enzyme dihydroorotate dehydrogenase (DHODH) which catalyses the rate-limiting step of pyrimidine biosynthesis and is an essential enzyme in the malaria parasite. There are currently several Plasmodium-selective DHODH inhibitors under development. To investigate the potential for drug resistance against DHODH inhibitors in vitro resistance selections were carried out using known inhibitors from different structural classes [1]. These studies identified point mutations in the drug binding site which lead to reduced sensitivity to the inhibitors, and in some cases increased sensitivity to a different inhibitor, suggesting a novel combination therapy approach to combat resistance. To help understand the significance of the inhibitor binding site mutations we determined the crystal structures of P. falciparum DHODH in complex with the inhibitors Genz-669178, IDI-6253 and IDI-6273. Co-crystallisation experiments led to a new crystal form in each case. Here we describe the crystal structures, the binding modes of the inhibitors and the great flexibility of the binding site, which is able to adjust to accommodate different inhibitor series. The structural role of the resistance mutations is also discussed.

scholarly journals Use of Crystallography and Molecular Modeling for the Inhibition of the Botulinum Neurotoxin A Protease

2021 ◽  
Author(s):  
Lewis Turner ◽  
Alexander Lund Nielsen ◽  
Lucy Lin ◽  
Antonio J. Campedelli ◽  
Nicholas Silvaggi ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Crystal Structures ◽  
Botulinum Neurotoxin ◽  
Enzyme Inhibitor ◽  
Binding Modes ◽  
Botulinum Neurotoxin A ◽  
Inhibitor Binding

We have used crystal structures and molecular modeling to evaluate inhibitor binding modes and design a series of compounds to take advantage of a new, cryptic, hydrophobic sub-pocket. This is a classical SBDD approach to improving enzyme/inhibitor interactions.

scholarly journals Cheminformatics Modeling of Closantel Analogues for Treating River Blindness

2020 ◽  
Author(s):  
Melaine A. Kuenemann ◽  
Phyo Phyo Zin ◽  
Sravya Kuchibhotla ◽  
Denis Fourches
Keyword(s):  
Active Site ◽  
Structural Changes ◽  
Parasitic Nematode ◽  
Chemical Space ◽  
Therapeutic Agents ◽  
Binding Modes ◽  
River Blindness ◽  
Structure Activity ◽  
Potential Binding ◽  
Biological Target

<p></p><p>Onchocerciasis (also known as river blindness<i>)</i> is a neglected tropical disease caused by the <i>Onchocerca volvulus</i> parasitic nematode. Currently, the only approved drug for treating this disease is ivermectin, which is a broad-spectrum antiparasitic agent. However, signs of resistance towards ivermectin have started to emerge. New therapeutic agents are thus urgently needed. The OvCHT1 chitinase enzyme from <i>O. volvulus</i> has been established as a relevant biological target for combatting river blindness. The veterinary anthelmintic drug closantel has been found to be a potent, micro-molar OvCHT1 inhibitor. Herein, we investigated the chemical space of closantel and all its synthesized analogues, focusing on the analysis of their potential binding modes towards OvCHT1. First, we conducted an unsupervised hierarchical clustering to group highly similar analogues and explore structure-activity relationships. Second, we conducted a structure-based molecular docking to predict and study the binding modes of all 57 closantel analogues in the active site of OvCHT1. Third, we screened more than 4 million lead-like compounds from the ZINC library to identify other structurally similar ligands that could potentially bind to OvCHT1. The cheminformatics analysis of the closantel analogues illustrated how minor structural changes in closantel analogues can impact their OvCHT1 activity.</p><p></p>

Supercooling of liquids

1952 ◽  
Vol 215 (1120) ◽  
pp. 43-46 ◽  
Keyword(s):  
Crystal Structures ◽  
Recent Change ◽  
The Other ◽  
Theoretical Interpretation ◽  
Experimental Fact ◽  
X Ray Diffraction ◽  
Diffraction Patterns ◽  
The One ◽  
The Right ◽  
Complex Crystal

I shall concentrate upon reviewing the important recent change in our appreciation of the facts of supercooling which has been brought about particularly by the work of Turnbull at the General Electric Research Laboratory in Schenectady. I suppose that most of us, talking about supercooling a couple of years ago, would have divided substances into two classes, one with simple crystal structures like gold, and all the other ‘good’ metals on the one hand, and those with complex crystal structures, such as glycerol and the silicates on the other; saying that whereas the latter class can be very much supercooled, and will form glasses, the former class can only be supercooled a very few degrees. Then we would have added that there are some ‘ bad ’ metals, with moderately complex crystal structures, such as antimony or bismuth, which can be supercooled some tens of degrees, forming an intermediate class. I think we would then have added that this is quite comprehensible. In particular, that the X-ray diffraction patterns of the monatomic liquids show us that most of the atoms have the right numbers of nearest neighbours in a first co-ordination shell, all ready in place to start the growth of a crystal; which readily explains why these substances cannot be supercooled very much—a nice simple experimental fact, with a straightforward theoretical interpretation—and both are wrong.

scholarly journals Structural basis of AdoMet-dependent aminocarboxypropyl transfer reaction catalyzed by tRNA-wybutosine synthesizing enzyme, TYW2

2009 ◽  
Vol 106 (37) ◽  
pp. 15616-15621 ◽  
Author(s):  
Masataka Umitsu ◽  
Hiroshi Nishimasu ◽  
Akiko Noma ◽  
Tsutomu Suzuki ◽  
Ryuichiro Ishitani ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Binding Pocket ◽  
Structural Basis ◽  
Binding Modes ◽  
Substrate Binding Pocket ◽  
Methyl Group ◽  
Group Transfer ◽  
Canonical Class ◽  
Functional Analyses

S-adenosylmethionine (AdoMet) is a methyl donor used by a wide variety of methyltransferases, and it is also used as the source of an α-amino-α-carboxypropyl (“acp”) group by several enzymes. tRNA-yW synthesizing enzyme-2 (TYW2) is involved in the biogenesis of a hypermodified nucleotide, wybutosine (yW), and it catalyzes the transfer of the “acp” group from AdoMet to the C7 position of the imG-14 base, a yW precursor. This modified nucleoside yW is exclusively located at position 37 of eukaryotic tRNAPhe, and it ensures the anticodon-codon pairing on the ribosomal decoding site. Although this “acp” group has a significant role in preventing decoding frame shifts, the mechanism of the “acp” group transfer by TYW2 remains unresolved. Here we report the crystal structures and functional analyses of two archaeal homologs of TYW2 from Pyrococcus horikoshii and Methanococcus jannaschii. The in vitro mass spectrometric and radioisotope-labeling analyses confirmed that these archaeal TYW2 homologues have the same activity as yeast TYW2. The crystal structures verified that the archaeal TYW2 contains a canonical class-I methyltransferase (MTase) fold. However, their AdoMet-bound structures revealed distinctive AdoMet-binding modes, in which the “acp” group, instead of the methyl group, of AdoMet is directed to the substrate binding pocket. Our findings, which were confirmed by extensive mutagenesis studies, explain why TYW2 transfers the “acp” group, and not the methyl group, from AdoMet to the nucleobase.

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