Design and synthesis of a novel inhibitor of T. Viride chitinase through an in silico target fishing protocol

Maccari, Giorgio; Deodato, Davide; Fiorucci, Diego; Orofino, Francesco; Truglio, Giuseppina I.; Pasero, Carolina; Martini, Riccardo; Luca, Filomena De; Docquier, Jean Denis; Botta, Maurizio

doi:10.1016/j.bmcl.2017.06.016

Cited by 11 publications

(11 citation statements)

References 27 publications

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“…As regards the MoA of the amidinoureas class, it is still under investigation, however, in-depth studies seem to confirm an intracellular accumulation of these derivatives [21] and specific interaction with cell structures such as receptors or enzymes, as found through the previously described in silico target fishing protocol [23]. However, what we expect for amidinoureas is an innovative MoA, not shared with current antifungals, since suggested by the notable activity profile found in drug-resistant fungal strains, especially those overexpressing CDR efflux pumps [21].…”

Section: Introductionmentioning

confidence: 84%

Focused library of phenyl-fused macrocyclic amidinoureas as antifungal agents

et al. 2022

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The rise of antimicrobial-resistant phenotypes and the spread of the global pandemic of COVID-19 are worsening the outcomes of hospitalized patients for invasive fungal infections. Among them, candidiases are seriously worrying, especially since the currently available drug armamentarium is extremely limited. We recently reported a new class of macrocyclic amidinoureas bearing a guanidino tail as promising antifungal agents. Herein, we present the design and synthesis of a focused library of seven derivatives of macrocyclic amidinoureas, bearing a second phenyl ring fused with the core. Biological activity evaluation shows an interesting antifungal profile for some compounds, resulting to be active on a large panel of Candida spp. and C. neoformans. PAMPA experiments for representative compounds of the series revealed a low passive diffusion, suggesting a membrane-based mechanism of action or the involvement of active transport systems. Also, compounds were found not toxic at high concentrations, as assessed through MTT assays.

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Section: Introductionmentioning

confidence: 84%

Focused library of phenyl-fused macrocyclic amidinoureas as antifungal agents

et al. 2022

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“…Another application is in silico target fishing or the identification of protein targets of orphan chemical compounds. In one recent research, the target of anti-fungal macrocycle amidinoureas was identified following a shape similarity screening (Maccari et al, 2017 ). The representative structure from a series of macrocycle amidinoureas was used as a query to obtain most similar crystallographic ligand from all solved crystal structures.…”

Section: Application Of Shape Similarity Methods In Drug Discoverymentioning

confidence: 99%

Advances in the Development of Shape Similarity Methods and Their Application in Drug Discovery

2018

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Molecular similarity is a key concept in drug discovery. It is based on the assumption that structurally similar molecules frequently have similar properties. Assessment of similarity between small molecules has been highly effective in the discovery and development of various drugs. Especially, two-dimensional (2D) similarity approaches have been quite popular due to their simplicity, accuracy and efficiency. Recently, the focus has been shifted toward the development of methods involving the representation and comparison of three-dimensional (3D) conformation of small molecules. Among the 3D similarity methods, evaluation of shape similarity is now gaining attention for its application not only in virtual screening but also in molecular target prediction, drug repurposing and scaffold hopping. A wide range of methods have been developed to describe molecular shape and to determine the shape similarity between small molecules. The most widely used methods include atom distance-based methods, surface-based approaches such as spherical harmonics and 3D Zernike descriptors, atom-centered Gaussian overlay based representations. Several of these methods demonstrated excellent virtual screening performance not only retrospectively but also prospectively. In addition to methods assessing the similarity between small molecules, shape similarity approaches have been developed to compare shapes of protein structures and binding pockets. Additionally, shape comparisons between atomic models and 3D density maps allowed the fitting of atomic models into cryo-electron microscopy maps. This review aims to summarize the methodological advances in shape similarity assessment highlighting advantages, disadvantages and their application in drug discovery.

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“…The screening consisted of a combination of shape similarity, inverse docking and consensus scoring, and highlighted the enzyme chitinase from Trichoderma viride as the possible pharmacological target of test molecules, as further verified experimentally. 40 MD simulations coupled with X-ray structural analysis was recently used to understand the basis of PPI in 14−3−3 from Giardia duodenalis (g14−3−3), a protozoan parasite responsible for widespread gastrointestinal diarrheal illness. A number of molecular simulations were carried out on the full-length homodimeric structure of g14−3−3 and were coupled with in depth simulations of isolated oligopeptides representing the connection between helices α8 and α9 of g14−3−3.…”

Section: ■ Antiviral Agentsmentioning

confidence: 99%