Cracking the chaperone code through the computational microscope.

The heat shock protein 90 kDa (Hsp90) chaperone machinery plays a crucial role in maintaining cellular homeostasis. Beyond its traditional role in protein folding, Hsp90 is integral to key pathways influencing cellular function in health and disease. Hsp90 operates through the modular assembly of large multiprotein complexes, with their composition, stability, and localization adapting to the cell's needs.

Conformational Dynamics, Energetics, and the Divergent Evolution of Allosteric Regulation: The Case of the Yeast MAPK Family.

Allosteric mechanisms provide finely-tuned control over signalling proteins. Proteins of the same family may share high sequence identity and structural similarity but show distinct traits of allosteric control and evolutionary divergent regulation. Revealing the determinants of such properties may be important to understand the molecular bases of different regulatory pathways.

Computational Methods in Immunology and Vaccinology: Design and Development of Antibodies and Immunogens.

The design of new biomolecules able to harness immune mechanisms for the treatment of diseases is a prime challenge for computational and simulative approaches. For instance, in recent years, antibodies have emerged as an important class of therapeutics against a spectrum of pathologies. In cancer, immune-inspired approaches are witnessing a surge thanks to a better understanding of tumor-associated antigens and the mechanisms of their engagement or evasion from the human immune system.

A focus on the biological targets for coinage metal-NHCs as potential anticancer complexes.

Metal complexes of N-heterocyclic carbene (NHC) ligands are the object of increasing attention for therapeutic purposes. Among the different metal centres, interest on Au-based compounds started with the application as anti-arthritis drugs. On the other hand, Ag(I) antimicrobial properties have been known for a long time.

On the Different Mode of Action of Au(I)/Ag(I)-NHC Bis-Anthracenyl Complexes Towards Selected Target Biomolecules.

Gold and silver N-heterocyclic carbenes (NHCs) are emerging for therapeutic applications. Multiple techniques are here used to unveil the mechanistic details of the binding to different biosubstrates of bis(1-(anthracen-9-ylmethyl)-3-ethylimidazol-2-ylidene) silver chloride [Ag(EIA)]Cl and bis(1-(anthracen-9-ylmethyl)-3-ethylimidazol-2-ylidene) gold chloride [Au(EIA)]Cl. As the biosubstrates, we tested natural double-stranded DNA, synthetic RNA polynucleotides (single-poly(A), double-poly(A)poly(U) and triple-stranded poly(A)2poly(U)), DNA G-quadruplex structures (G4s), and bovine serum albumin (BSA) protein.

I Radiolabeling of a Au -NHC Complex for In Vivo Biodistribution Studies.

Au complexes with N-heterocyclic carbene (NHC) ligands have shown remarkable potential as anticancer agents, yet their fate in vivo has not been thoroughly examined and understood. Reported herein is the synthesis of new Au -NHC complexes by direct oxidation with radioactive [ I]I as a valuable strategy to monitor the in vivo biodistribution of this class of compounds using positron emission tomography (PET). While in vitro analyses provide direct evidence for the importance of Au -to-Au reduction to achieve full anticancer activity, in vivo studies reveal that a fraction of the Au -NHC prodrug is not immediately reduced after administration but able to reach the major organs before metabolic activation.

Cytotoxic Ag(I) and Au(I) NHC-carbenes bind DNA and show TrxR inhibition.

A silver(I) and a gold(I) complex of the fluorescent N-heterocyclic carbenic (NHC) ligand 1-(9-anthracenylmethyl)-3-(3-trimethylsilyl-2-propynil)-benzimidazol-2-ylidene have been synthesized and characterized. These compounds show cytotoxicity in the micromolar range and higher antiproliferative properties than cisplatin (CDDP) against several tumour cell lines such as SW480 (colon), A549 (lung) and HepG2 (liver). Both metal complexes are successfully internalized by SW480 cells being the silver compound the most accumulated.

DNA interaction of a fluorescent, cytotoxic pyridinimino platinum(II) complex.

New pyridinimino complexes of platinum(II) [PtCl(N^N-R)] (N^N = 2-pyridylmethanimino, R = -(CH)O(CH)OH, -(CH)O(CH)OCHPyr), Pyr = pyren-1-yl) have been prepared. They are characterized by a dioxygenated alkyl side chain and, in one case, by a fluorescent terminal 1-pyrenyl residue. The complexes were characterized by elemental analysis, IR, H-, C-and Pt NMR spectroscopies.

Interaction of a gold(i) dicarbene anticancer drug with human telomeric DNA G-quadruplex: solution and computationally aided X-ray diffraction analysis.

The bis carbene gold(i) complex [Au(1-butyl-3-methyl-2-ylidene)2]PF6, ([Au(NHC)2]PF6 hereafter), holds remarkable interest as a perspective anticancer agent. The compound is stable under physiological like conditions: its original structure is retained even in the presence of excess glutathione (GSH). Previous studies revealed its high cytotoxicity in vitro that correlates with the impairment of crucial metabolic and enzymatic cellular processes (Magherini et al.

Anticancer Gold N-Heterocyclic Carbene Complexes: A Comparative in vitro and ex vivo Study.

A series of organometallic Au N-heterocyclic carbene (NHC) complexes was synthesized and characterized for anticancer activity in four human cancer cell lines. The compounds' toxicity in healthy tissue was determined using precision-cut kidney slices (PCKS) as a tool to determine the potential selectivity of the gold complexes ex vivo. All evaluated compounds presented cytotoxic activity toward the cancer cells in the nano- or low micromolar range.