<i>In Silico</i> Identification of Piperidinyl-amine Derivatives as Novel Dual Binders of Oncogene c-myc/c-Kit G-quadruplexes

Rocca, Roberta; Moraca, Federica; Costa, Giosuè; Talarico, Carmine; Ortuso, Francesco; Ros, Silvia Da; Nicoletto, Giulia; Sissi, Claudia; Alcaro, Stefano; Artese, Anna

doi:10.1021/acsmedchemlett.8b00275

Cited by 20 publications

(17 citation statements)

References 47 publications

(74 reference statements)

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“…From crystallographic data, SBDD can reveal the ligands’ binding mode in the target pocket, hence providing one of the most favorable ways for the design of potential high-affinity ligands. SBDD, in addition to being preferred by drug designers because of its higher success rate, has emerged as the most innovative tool used in the pharmaceutical industry helping researchers to individuate many lead compounds in different research fields [ 128 , 129 , 130 , 131 , 132 , 133 , 134 ].…”

Section: Enhancing Jakis Discovery Through Structure-based Drug Dementioning

confidence: 99%

Inside Perspective of the Synthetic and Computational Toolbox of JAK Inhibitors: Recent Updates

et al. 2020

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The mechanisms of inflammation and cancer are intertwined by complex networks of signaling pathways. Dysregulations in the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway underlie several pathogenic conditions related to chronic inflammatory states, autoimmune diseases and cancer. Historically, the potential application of JAK inhibition has been thoroughly explored, thus triggering an escalation of favorable results in this field. So far, five JAK inhibitors have been approved by the Food and Drug Administration (FDA) for the treatment of different diseases. Considering the complexity of JAK-depending processes and their involvement in multiple disorders, JAK inhibitors are the perfect candidates for drug repurposing and for the assessment of multitarget strategies. Herein we reviewed the recent progress concerning JAK inhibition, including the innovations provided by the release of JAKs crystal structures and the improvement of synthetic strategies aimed to simplify of the industrial scale-up.

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Section: Enhancing Jakis Discovery Through Structure-based Drug Dementioning

confidence: 99%

Inside Perspective of the Synthetic and Computational Toolbox of JAK Inhibitors: Recent Updates

et al. 2020

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“…As for computational methods, the identification of new hit compounds by a virtual screening (VS) approach can represent a crucial step in early-stage of drug discovery. In fact, theoretical studies, based on chemoinformatics and bioinformatics methods, are capable to speed up the identification of bioactive compounds, by testing with in vitro and in vivo assays only the most promising candidates selected through in silico simulations [17][18][19][20][21][22][23]. In this regard, SBVS is a computational approach useful to identify novel bioactive ligands against a certain target or a set of interesting targets, getting information from the three-dimensional (3D) structures of proteins or nucleic acids, obtained from X-ray or NMR methodologies.…”

Section: Introductionmentioning

confidence: 99%

Multi-Targeting Bioactive Compounds Extracted from Essential Oils as Kinase Inhibitors

et al. 2020

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Essential oils (EOs) are popular in aromatherapy, a branch of alternative medicine that claims their curative effects. Moreover, several studies reported EOs as potential anti-cancer agents by inducing apoptosis in different cancer cell models. In this study, we have considered EOs as a potential resource of new kinase inhibitors with a polypharmacological profile. On the other hand, computational methods offer the possibility to predict the theoretical activity profile of ligands, discovering dangerous off-targets and/or synergistic effects due to the potential multi-target action. With this aim, we performed a Structure-Based Virtual Screening (SBVS) against X-ray models of several protein kinases selected from the Protein Data Bank (PDB) by using a chemoinformatics database of EOs. By evaluating theoretical binding affinity, 13 molecules were detected among EOs as new potential kinase inhibitors with a multi-target profile. The two compounds with higher percentages in the EOs were studied more in depth by means Induced Fit Docking (IFD) protocol, in order to better predict their binding modes taking into account also structural changes in the receptor. Finally, given its good binding affinity towards five different kinases, cinnamyl cinnamate was biologically tested on different cell lines with the aim to verify the antiproliferative activity. Thus, this work represents a starting point for the optimization of the most promising EOs structure as kinase inhibitors with multi-target features.

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“…In parallel to the repurposing paradigm, the application of in silico techniques for identifying new hit compounds is a very profitable approach [ 31 ], reducing cost and time of research-associated activities [ 32 , 33 , 34 , 35 ]. In particular, structure-based virtual screening (SBVS) is a powerful in silico tool for the identification of novel bioactive ligands and is very useful in predicting the best interaction between ligands and molecular targets [ 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ].…”

Section: Introductionmentioning

confidence: 99%

Natural Products Extracted from Fungal Species as New Potential Anti-Cancer Drugs: A Structure-Based Drug Repurposing Approach Targeting HDAC7

et al. 2020

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Mushrooms can be considered a valuable source of natural bioactive compounds with potential polypharmacological effects due to their proven antimicrobial, antiviral, antitumor, and antioxidant activities. In order to identify new potential anticancer compounds, an in-house chemical database of molecules extracted from both edible and non-edible fungal species was employed in a virtual screening against the isoform 7 of the Histone deacetylase (HDAC). This target is known to be implicated in different cancer processes, and in particular in both breast and ovarian tumors. In this work, we proposed the ibotenic acid as lead compound for the development of novel HDAC7 inhibitors, due to its antiproliferative activity in human breast cancer cells (MCF-7). These promising results represent the starting point for the discovery and the optimization of new HDAC7 inhibitors and highlight the interesting opportunity to apply the “drug repositioning” paradigm also to natural compounds deriving from mushrooms.

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In Silico Identification of Piperidinyl-amine Derivatives as Novel Dual Binders of Oncogene c-myc/c-Kit G-quadruplexes

Cited by 20 publications

References 47 publications

Inside Perspective of the Synthetic and Computational Toolbox of JAK Inhibitors: Recent Updates

Inside Perspective of the Synthetic and Computational Toolbox of JAK Inhibitors: Recent Updates

Multi-Targeting Bioactive Compounds Extracted from Essential Oils as Kinase Inhibitors

Natural Products Extracted from Fungal Species as New Potential Anti-Cancer Drugs: A Structure-Based Drug Repurposing Approach Targeting HDAC7

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