1,548 research outputs found
An omics perspective to the molecular mechanisms of anticancer metallo-drugs in the computational microscope era
No full textIntroduction: Metallo-drugs have attracted enormous interest for cancer treatment. The achievements of this drug-type are summarized by the success story of cisplatin. That being said, there have been many drawbacks with its clinical use, which prompted decades worth of research efforts to move towards safer and more effective agents, either containing platinum or different metals.
Areas covered: In this review, the authors provide an atomistic picture of the molecular mechanisms involving selected metallo-drugs from structural and molecular simulation studies. They also provide an omics perspective, pointing out many unsettled aspects of the most relevant families of metallo-drugs at an epigenetic level.
Expert opinion: Molecular simulations are able to provide detailed information at atomistic and temporal (ps) resolutions that are rarely accessible to experiments. The increasing accuracy of computational methods and the growing performance of computational platforms, allow us to mirror wet lab experiments in silico. Consequently, the molecular mechanisms of drugs action/failure can be directly viewed on a computer screen, like a 'computational microscope', allowing us to harness this knowledge for the design of the next-generation of metallo-drugs
The avidin‐theophylline complex: A structural and computational study
No full text: The interaction between avidin and its counterpart biotin is one of central importance in biology and has been reproposed and studied at length. However, the binding pocket of avidin is prone to promiscuous binding, able to accommodate even non-biotinylated ligands. Comprehending the factors that distinguish the extremely strong interaction with biotin to other ligands is an important step to fully picture the thermodynamics of these low-affinity complexes. Here, we present the complex between chicken white egg avidin and theophylline (TEP), the xanthine derivative used in the therapy of asthma. In the crystal structure, TEP lies in the biotin-binding pocket with the same orientation and planarity of the aromatic ring of 8-oxodeoxyguanosine. Indeed, its affinity for avidin measured by isothermal titration calorimetry is in the same μM range as those obtained for the previously characterized nucleoside derivatives. By the use of molecular dynamic simulations, we have investigated the most important intermolecular interactions occurring in the avidin-TEP binding pocket and compared them with those obtained for the avidin 8-oxodeoxyguanosine and avidin-biotin complexes. These results testify the capability of avidin to complex purely aromatic molecules
Role of computational and structural biology in the development of small-molecule modulators of the spliceosome
No full textRNA splicing is a pivotal step of eukaryotic gene expression during which the introns are excised from the precursor (pre-)RNA and the exons are joined together to form mature RNA products (i.e a protein-coding mRNA or long non-coding (lnc)RNAs). The spliceosome, a complex ribonucleoprotein machine, performs pre-RNA splicing with extreme precision. Deregulated splicing is linked to cancer, genetic, and neurodegenerative diseases. Hence, the discovery of small-molecules targeting core spliceosome components represents an appealing therapeutic opportunity
Anticancer Activity, Reduction Mechanism and G-Quadruplex DNA Binding of a Redox-Activated Platinum(IV)–Salphen Complex
No full textAiming at reducing the unselective cytotoxicity of Pt(II) chemotherapeutics, a great deal
of effort has been concentrated into the design of metal‐containing drugs with different anticancer mechanisms of action. Inert Pt(IV) prodrugs have been proposed to be a valid alternative as they are activated by reduction directly into the cell releasing active Pt(II) species. On the other hand, a promising strategy for designing metallodrugs is to explore new potential biological targets rather than canonical B‐DNA. G‐quadruplex nucleic acid, obtained by self‐assembly of guanine‐rich nucleic acid sequences, has recently been considered an attractive target for anticancer drug design.
Therefore, compounds capable of binding and stabilizing this type of DNA structure would be greatly beneficial in anticancer therapy. Here, computational analysis reports the mechanism of action of a recently synthesized Pt(IV)–salphen complex conjugating the inertness of Pt(IV) prodrugs with the ability to bind G‐quadruplexes of the corresponding Pt(II) complex. The reduction mechanism of the Pt(IV) complex with a biological reducing agent was investigated in depth by means of DFT, whereas classical MD simulations were carried out to shed light into the binding mechanism of the released Pt(II) complex. The results show that the Pt(IV) prodrug may be reduced by both inner‐ and outer‐sphere mechanisms, and the active Pt(II) complex, as a function
of its protonation state, stabilizes the G‐quadruplex DNA prevalently, either establishing π‐stacking nteractions with the terminal G‐tetrad or through electrostatic interactions along with H‐bonds formation
The history of the Romano famili and "Angelo, tyran de Padoue" by Victor Hugo.
No full textreservedVictor Hugo, nel dramma Angelo, tyran de Padue, ricama tre diverse epoche storiche: i primi decenni dell’Ottocento, a lui contemporanei; la metà del Cinquecento, prescelta per lo svolgimento dell’azione drammatica; il tardo Medioevo evinto dai personaggi principali che compongono il racconto. Tuttavia, l’interesse storico e prettamente romantico verso il periodo medievale assume in quest’opera una rilevanza primaria. Tra le tante casate del nord Italia nominate dall’autore nell’opera, una su tutte sembra essere davvero simbolica. Particolarmente interessante è stato comprendere come la storia della famiglia da Romano costituisca il fulcro della costruzione drammaturgica. Ezzelino III e Cunizza da Romano sono elevati a emblema della poetica romantica e divengono funzionali al messaggio politico e sociale dell’autore.Victor Hugo, in his play Angelo, tyran de Padue, embroiders three different historical epochs: the first decades of the 19th century, contemporary with him; the middle of the 16th century, chosen for the unfolding of the dramatic action; and the late Middle Ages evoked by the main characters in the story. However, the historical and purely romantic interest in the medieval period takes on primary importance in this work. Of the many northern Italian lineages named by the author in the work, one in particular seems to be truly symbolic. It was particularly interesting to understand how the history of the da Romano family forms the core of the dramaturgical construction. Ezzelino III and Cunizza da Romano are elevated to emblems of romantic poetics and become functional to the author's political and social message
The Interaction of Metal Complexes with G-quadruplex DNA
No full textUn approccio computazionale è stato proposto per lo studio dell’interazione di complessi metallici di basi di Schiff con DNA. Nel capitolo 2, è stato investigato il meccanismo di azione di complessi di Nichel(II), Rame(II) e Zinco(II) con B e G-quadruplex DNA. Il G-quadruplex è una conformazione non canonica adottata da particolari sequenze ricche in guanina. Recentemente, è stata dimostrata la sua esistenza in cellule umane, in regioni telomeriche e non telomeriche, ed è stato proposto come un possibile target per una nuova categoria di agenti antineoplastici. I capitoli successivi sono basati su dati raccolti durante due periodi di ricerca all’estero.
Nel capitolo 3, basato sugli studi eseguiti presso l’Università tecnica di Braunschweig, verrà mostrato come i campi di forza, oggigiorno di uso comune in Chimica/Biofisica Computazionale, siano in grado di riprodurre correttamente la stabilità relativa di G-quadruplex modello. Inoltre, è stata studiata in dettaglio l’interazione di una classe di leganti organici, noti G-quadruplex binders, con un modello di quadruplex parallelo. L’approccio computazionale ha messo in evidenza l’importanza del considerare esplicitamente la protonazione dei leganti.
Nel capitolo 4, risultato di una COST Short-Term Scientific Mission in Francia presso l’Universitè de Lorraine, è descritta la procedura usata per riprodurre gli spettri di Dicroismo Circolare delle principali conformazioni dei G-quadruplex.A computational approach was proposed to study the binding and the stability of metal complex-nucleic acid supramolecular systems. In particular, the interaction of transition metal complexes with DNA structures named “G-quadruplexes” was considered. G-quadruplex conformations are present in telomeres and several oncogenes and they are involved in the inhibition of telomerase, a protein responsible for immortalization of cancer cells. The main purpose of the project was then to provide a computational tool to design chemical compounds able to selectively
stabilize G-quadruplex structures
Cancer-Related Mutations Alter RNA-Driven Functional Cross-Talk Underlying Premature-Messenger RNA Recognition by Splicing Factor SF3b
No full textThe pillar of faithful premature-messenger (pre-mRNA)splicingis the precise recognition of key intronic sequences by specific splicingfactors. The heptameric splicing factor 3b (SF3b) recognizes the branchpoint sequence (BPS), a key part of the 3 & PRIME; splice site. SF3bcontains SF3B1, a protein holding recurrent cancer-associated mutations.Among these, K700E, the most-frequent SF3B1 mutation, triggers aberrantsplicing, being primarily implicated in hematologic malignancies.Yet, K700E and the BPS recognition site are 60 & ANGS; apart, suggestingthe existence of an allosteric cross-talk between the two distal spots.Here, we couple molecular dynamics simulations and dynamical networktheory analysis to unlock the molecular terms underpinning the impactof SF3b splicing factor mutations on pre-mRNA selection. We establishthat by weakening and remodeling interactions of pre-mRNA with SF3b,K700E scrambles RNA-mediated allosteric cross-talk between the BPSand the mutation site. We propose that the altered allostery contributesto cancer-associated missplicing by mutated SF3B1. This finding broadensour comprehension of the elaborate mechanisms underlying pre-mRNAmetabolism in eukaryotes
Rationalizing the structural basis of organic-platinum hybrid complexes binding towards quadruplex-duplex hybrids through all-atom simulations
No full textGuanine-rich sequences containing complementary base pairs can fold into non-canonical quadruplex-duplex hybrid (QDH) conformations. These structures possess unique structural features, leading to the presence of a peculiar binding pocket that can be distinguished from a canonical double helix or a G-quadruplex (G4) structure. Recently, two organic-metal hybrid platinum complexes, able to selectively and strongly recognize a particular type of QDH with a lateral duplex stem-loop, were reported in the literature. However, solution structures are not available for all the investigated compounds, leaving unanswered questions on the structural traits underlying the different binding affinity of these complexes. In this work, we address this gap using all-atom simulations to unravel the key features driving the high selectivity of these organic‐platinum hybrid complexes at an atomistic level. In particular, their binding affinity depends on a delicate balance between the extended π-π stacking interactions performed in the G4-duplex binding pocket and the capacity to form stable hydrogen bonds with the surrounding nucleobases. Thus, our findings provide essential insights to guide the rational design of novel compounds that selectively target QDH structures
Michael Angelo Caruso, international author, consultant, and speaker on Campus
No full textTollefson, Elizabeth. (2013). Michael Angelo Caruso, international author, consultant, and speaker on Campus. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/223386
Oltre i confini della razionalità
No full text- Il contributo di Angelo Volpe prende in esame fondamentalmen-te due oggetti: primo, la potenzialità indiscussa nella sociologia contemporanea degli approcci individualistici e razionali e, secondo, la necessità di trascendere la gabbia stessa della razionalità e di andare oltre. Ciò che l’autore auspica è la realizzazione di un “modello a spettro intero” per l’analisi dei fatti sociali, un modello che possa espandere il raggio d’azione della comprensione sociologica al di là di ciò che possiamo vedere e misurare razionalmente.
- The contribution of Angelo Volpe essentially examines two objects: first, the unquestioned potentiality in contemporary sociology of individualistic and rational approaches, and, second, the need to transcend the very cage of rationality and go further. What the author hopes is the realization of a "full-spectrum model" for the analysis of social events, a model that can expand the scope of sociological understanding beyond what we can see and measure rationally
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