Structural and computational characterization of a bridging zwitterionic-amidoxime uranyl complex

The protozoan parasite Trypanosoma brucei is the etiological agent of human African trypanosomiasis (HAT). HAT, together with other neglected tropical diseases, causes serious health and economic issues, especially in tropical and subtropical areas. The classical antifolates targeting dihydrofolate reductase (DHFR) are ineffective towards trypanosomatid parasites owing to a metabolic bypass by the expression of pteridine reductase 1 (PTR1). The combined inhibition of PTR1 and DHFR activities in Trypanosoma parasites represents a promising strategy for the development of new effective treatments for HAT. To date, only monocyclic and bicyclic aromatic systems have been proposed as inhibitors of T. brucei PTR1 (TbPTR1); nevertheless, the size of the catalytic cavity allows the accommodation of expanded molecular cores. Here, an innovative tricyclic-based compound has been explored as a TbPTR1-targeting molecule and its potential application for the development of a new class of PTR1 inhibitors has been evaluated. 2,4-Diaminopyrimido[4,5-b]indol-6-ol (1) was designed and synthesized, and was found to be effective in blocking TbPTR1 activity, with a K i in the low-micromolar range. The binding mode of 1 was clarified through the structural characterization of its ternary complex with TbPTR1 and the cofactor NADP(H), which was determined to 1.30 Å resolution. The compound adopts a substrate-like orientation inside the cavity that maximizes the binding contributions of hydrophobic and hydrogen-bond interactions. The binding mode of 1 was compared with those of previously reported bicyclic inhibitors, providing new insights for the design of innovative tricyclic-based molecules targeting TbPTR1.

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Characterization of platinum(II) complexes exhibiting inhibitory activity against the 20S proteasome

Royal Society Open Science ◽

10.1098/rsos.200545 ◽

2020 ◽

Vol 7 (8) ◽

pp. 200545

Author(s):

Tatsuto Kiwada ◽

Hiromu Katakasu ◽

Serina Okumura ◽

Akira Odani

Keyword(s):

Inhibitory Activity ◽

Chemical Structure ◽

Competitive Inhibition ◽

Proteasome Inhibitors ◽

Platinum Complex ◽

Platinum Complexes ◽

Binding Mode ◽

Structure Activity Relationships ◽

Structure Activity

Proteasome inhibitors are useful for biochemical research and clinical treatment. In our previous study, we reported that the 4N-coordinated platinum complexes with anthracenyl ring and heterocycle exhibited proteasome-inhibitory activity. In the present study, the structure–activity relationships and characterization of these complexes were determined for the elucidation of the role of aromatic ligands. Lineweaver–Burk analysis revealed that the chemical structure of heterocycles affects the binding mode of platinum complexes. Platinum complexes with anthracenyl ring and pyridine showed competitive inhibition, although platinum complexes with anthracenyl ring and phenanthroline showed non-competitive inhibition. The structure–activity relationships demonstrated that anthracenyl moiety plays a crucial role in proteasome-inhibitory activity. The platinum complexes with naphthyl or phenyl rings exhibited lower inhibitory activities than the platinum complex with anthracenyl ring. The reactivity with N-acetylcysteine varied according to the chemical structure of complexes.

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Computational characterization of the binding mode between oncoprotein Ets-1 and DNA-repair enzymes

Proteins Structure Function and Bioinformatics ◽

10.1002/prot.25578 ◽

2018 ◽

Vol 86 (10) ◽

pp. 1055-1063 ◽

Cited By ~ 1

Author(s):

Jerome de Ruyck ◽

Guillaume Brysbaert ◽

Vincent Villeret ◽

Marc Aumercier ◽

Marc F. Lensink

Keyword(s):

Dna Repair ◽

Binding Mode ◽

Dna Repair Enzymes ◽

Repair Enzymes

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Flavonoids as Putative Epi-Modulators: Insight into Their Binding Mode with BRD4 Bromodomains Using Molecular Docking and Dynamics

Biomolecules ◽

10.3390/biom8030061 ◽

2018 ◽

Vol 8 (3) ◽

pp. 61 ◽

Cited By ~ 9

Author(s):

Fernando Prieto-Martínez ◽

José Medina-Franco

Keyword(s):

Kinase Inhibitors ◽

Binding Mode ◽

Binding Modes ◽

Ligand Interaction ◽

Bet Inhibitors ◽

Protein Ligand Interaction ◽

Brd4 Inhibition ◽

Dynamics Simulations ◽

Insight Into

Flavonoids are widely recognized as natural polydrugs, given their anti-inflammatory, antioxidant, sedative, and antineoplastic activities. Recently, different studies showed that flavonoids have the potential to inhibit bromodomain and extraterminal (BET) bromodomains. Previous reports suggested that flavonoids bind between the Z and A loops of the bromodomain (ZA channel) due to their orientation and interactions with P86, V87, L92, L94, and N140. Herein, a comprehensive characterization of the binding modes of fisetin and the biflavonoid, amentoflavone, is discussed. To this end, both compounds were docked with BET bromodomain 4 (BRD4) using four docking programs. The results were post-processed with protein–ligand interaction fingerprints. To gain further insight into the binding mode of the two natural products, the docking results were further analyzed with molecular dynamics simulations. The results showed that amentoflavone makes numerous contacts in the ZA channel, as previously described for flavonoids and kinase inhibitors. It was also found that amentoflavone can potentially make contacts with non-canonical residues for BET inhibition. Most of these contacts were not observed with fisetin. Based on these results, amentoflavone was experimentally tested for BRD4 inhibition, showing activity in the micromolar range. This work may serve as the basis for scaffold optimization and the further characterization of flavonoids as BET inhibitors.

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Structural and Functional Characterization of the Human Thymidylate Synthase (hTS) Interface Variant R175C, New Perspectives for the Development of hTS Inhibitors

Molecules ◽

10.3390/molecules24071362 ◽

2019 ◽

Vol 24 (7) ◽

pp. 1362

Author(s):

Cecilia Pozzi ◽

Stefania Ferrari ◽

Rosaria Luciani ◽

Maria Costi ◽

Stefano Mangani

Keyword(s):

Thymidylate Synthase ◽

Active Site ◽

Functional Characterization ◽

Binding Mode ◽

Anticancer Chemotherapy ◽

Innovative Strategies ◽

X Ray Crystallography ◽

Site Targeting ◽

New Strategies

Human thymidylate synthase (hTS) is pivotal for cell survival and proliferation, indeed it provides the only synthetic source of dTMP, required for DNA biosynthesis. hTS represents a validated target for anticancer chemotherapy. However, active site-targeting drugs towards hTS have limitations connected to the onset of resistance. Thus, new strategies have to be applied to effectively target hTS without inducing resistance in cancer cells. Here, we report the generation and the functional and structural characterization of a new hTS interface variant in which Arg175 is replaced by a cysteine. Arg175 is located at the interface of the hTS obligate homodimer and protrudes inside the active site of the partner subunit, in which it provides a fundamental contribution for substrate binding. Indeed, the R175C variant results catalytically inactive. The introduction of a cysteine at the dimer interface is functional for development of new hTS inhibitors through innovative strategies, such as the tethering approach. Structural analysis, performed through X-ray crystallography, has revealed that a cofactor derivative is entrapped inside the catalytic cavity of the hTS R175C variant. The peculiar binding mode of the cofactor analogue suggests new clues exploitable for the design of new hTS inhibitors.

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