1,721,124 research outputs found
Small molecules modulation of 14-3-3 protein–protein interactions
No full text14-3-3 is a family of highly conserved regulatory proteins which is attracting a significant interest due to its potential role as target for pharmacological intervention against cancer and neurodegenerative disorders. Although modulating protein-protein interactions (PPI) is still conceived as a challenging task in drug discovery, in past few years peptide inhibitors and small molecular modulators of 14-3-3 PPI have been described. Here we examine structural and biological features of 14-3-3 and propose an overview on techniques used for discovering small molecular inhibitors and stabilizers of 14-3-3 PPI
Molecular Dynamics and DFT Study on HIV-1 Nucleocapsid Protein-7 in Complex with Viral Genome
No full textThe HIV-1 nucleocapsid protein-7 (NCp7) is a highly basic, small zinc-binding protein involved in both deoxyribonucleic (DNA) and ribonucleic (RNA) acids annealing and in viral particle maturation including genome encapsidation, with an additional chaperoning activity toward reverse transcriptase by promoting the two obligatory strand transfers during reverse transcription. Because of its interaction with highly conserved sequences of the HIV-1 genome, NCp7 is being considered a new potential drug target, resistant to mutation, for antiviral activity. The high flexibility of this protein has, however, limited the identification of structural determinants involved in the interaction with stranded sequences of DNA and RNA. Here, we provide a quantum mechanics (density functional theory) study of the zinc-binding motifs and a molecular dynamics simulation of the protein in complex with RNA and DNA, starting from available nuclear magnetic resonance (NMR) structures. Results show that the interaction between the NCp7 and the viral genome is probably based on electrostatic interactions due to a cluster of basic residues, which is reinforced by the exploitation of nonelectrostatic contacts that further stabilize the complexes. Moreover, a possible mechanism for DNA destabilization that involves amino acids T24 and R26 is also hypothesized. Finally, a network of hydrophobic and hydrogen-bond interactions for the stabilization of complexes with DNA and, especially, with RNA is described here for the first time. The complexes between NCp7 and both DNA and RNA, resulting from computer simulations, showed structural properties that are in agreement with most of the currently available molecular biology evidence and could be considered as reliable models (better than NMR structures currently available) for subsequent structure-based ligand design approaches
Perspectives in the treatment of antibiotic-resistant bacterial infections with active photodynamic partners within the framework of the EURESTOP COST Action (CA21145)
Full text linkThe European Network for diagnosis and treatment of antibiotic-resistant bacterial infections-EURESTOP COST Action CA21145 focuses on tackling the burden of antimicrobial resistance (AMR) and has gathered many members working on photodynamic approaches. This European consortium is presented here in the One Health context, to highlight the potential of antimicrobial photodynamic therapy (aPDT) in the fight against AMR
One hundred faces of cyclopamine
No full textThe natural steroidal alkaloid cyclopamine has been identified as the first inhibitor of the Hedgehog (Hh) signaling pathway, which is implicated in embryonic development and tumorigenesis, as well as is hyperactivated in cancer stem cells (CSCs). The list of Hh-dependent tumors is steadily growing, and it has been estimated that about 25% of all cancer deaths show signs of aberrant Hh pathway activation. Notably, cyclopamine has been found to exert anticancer activity against several types of human cancer and to inhibit CSCs proliferation, thus highlighting the druggability of the Hh pathway and paving new opportunities in anticancer drug discovery. The aim of the present work is to review the main synthetic strategies to cyclopamine and its derivatives, with particular emphasis on the challenging chemical modifications aimed at improving the biological activity of the molecule
Mycobacterial carbonic anhydrase inhibition with phenolic acids and esters: kinetic and computational investigations
No full textA series of phenolic acids and some of their esters, derivatives of caffeic, ferulic, and p-coumaric acid, was investigated for the inhibition of three β-carbonic anhydrases (CAs, EC 4.2.1.1) from the pathogenic bacterium Mycobacterium tuberculosis, Rv1248, Rv3588 and Rv3273 β-CAs. Some of these compounds were low micromolar inhibitors of the pathogenic enzymes and they did not show inhibitory activity against the human widespread cytosolic isoforms CA I and II. The binding mode of these inhibitors to two of the bacterial enzymes was investigated by computational approaches. We propose that the inhibitors anchor to the zinc-coordinated water molecule from the CA active site interfering with the nucleophilic attack of the zinc hydroxide on the substrate CO2. These compounds may be considered as interesting anti-mycobacterial lead compounds.
© 2016 The Royal Society of Chemistry
Targeting Protein-Protein and Protein-Nucleic Acid Interactions for Anti-HIV Therapy
No full textProtein-protein and protein-nucleic acid interactions are involved in many regulatory cellular pathways, playing a key role in cell growth and proliferation, as well as in the progression and development of various diseases such as infectious diseases. Especially in the anti-AIDS research, protein-protein and protein-nucleic acid complexes are being considered as promising targets for pharmaceutical interventions aimed at overcoming the drug resistance observed for most of the classic enzyme inhibitors. Consequently, more and more protein-protein and protein-nucleic acid interaction inhibitors have being identified and developed as candidate agents for antiretroviral therapy. Here, we review the state of the art in the discovery and development of protein-protein and protein-nucleic acid interaction inhibitors that block the main steps of the HIV-1 replication cycle, giving a medicinal chemistry-oriented view of strategies for inhibiting these regulatory interactions that are involved in the entry process, in the dimerization of reverse transcriptase and protease enzymes, and in the activity of the nucleocapsid protein by means of small molecular potential therapeutic agents
The Rise of Bacterial G‑Quadruplexes in Current Antimicrobial Discovery
Full text linkAntimicrobial resistance (AMR) is a silent critical issue that poses several challenges to health systems. While the discovery of novel antibiotics is currently stalled and prevalently focused on chemical variations of the scaffolds of available drugs, novel targets and innovative strategies are urgently needed to face this global threat. In this context, bacterial G-quadruplexes (G4s) are emerging as timely and profitable targets for the design and development of antimicrobial agents. Indeed, they are expressed in regulatory regions of bacterial genomes, and their modulation has been observed to provide antimicrobial effects with translational perspectives in the context of AMR. In this work, we review the current knowledge of bacterial G4s as well as their modulation by small molecules, including tools and techniques suitable for these investigations. Finally, we critically analyze the needs and future directions in the field, with a focus on the development of small molecules as bacterial G4s modulators endowed with remarkable drug-likeness
Predicting the Binding Mode of Known NCp7 Inhibitors To Facilitate the Design of Novel Modulators
No full textThe HIV-1 nucleocapsid protein (NCp7) is an emerging target for antiretroviral therapy. Five hits have been reported to inhibit the NCp7-viral nucleic acids interaction at micromolar concentrations. We used two computationally refined structures of NCp7 as receptors to propose a reliable binding pose for these compounds, by means of computational methods. Theoretical binding modes are in agreement with available experimental data. Results lay the foundations for a rationale development of more effective NCp7 inhibitor
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