1,721,052 research outputs found
Quinoline anticancer agents active on DNA and DNA-interacting proteins: From classical to emerging therapeutic targets
No full textQuinoline is one of the most important and versatile nitrogen heterocycles embodied in several biologically active molecules. Within the numerous quinolines developed as antiproliferative agents, this review is focused on compounds interfering with DNA structure or with proteins/enzymes involved in the regulation of double helix functional processes. In this light, a special focus is given to the quinoline compounds, acting with classical/well-known mechanisms of action (DNA intercalators or Topoisomerase inhibitors). In particular, the quinoline drugs amsacrine and camptothecin (CPT) have been studied as key lead compounds for the development of new agents with improved PK and tolerability properties. Moreover, notable attention has been paid to the quinoline molecules, which are able to interfere with emerging targets involved in cancer progression, as G-quadruplexes or the epigenetic ones (e.g.: histone deacetylase, DNA and histones methyltransferase). The antiproliferative and the enzymatic inhibition data of the reviewed compounds have been analyzed. Furthermore, concerning the SAR (structure-activity relationship) aspects, the most recurrent ligand-protein interactions are summarized, underling the structural requirements for each kind of mechanism of action
In Silico Insights into the SARS CoV-2 Main Protease Suggest NADH Endogenous Defences in the Control of the Pandemic Coronavirus Infection
Full text linkCOVID-19 is a pandemic health emergency faced by the entire world. The clinical treatment of the severe acute respiratory syndrome (SARS) CoV-2 is currently based on the experimental administration of HIV antiviral drugs, such as lopinavir, ritonavir, and remdesivir (a nucleotide analogue used for Ebola infection). This work proposes a repurposing process using a database containing approximately 8000 known drugs in synergy structure- and ligand-based studies by means of the molecular docking and descriptor-based protocol. The proposed in silico findings identified new potential SARS CoV-2 main protease (MPRO) inhibitors that fit in the catalytic binding site of SARS CoV-2 MPRO. Several selected structures are NAD-like derivatives, suggesting a relevant role of these molecules in the modulation of SARS CoV-2 infection in conditions of cell chronic oxidative stress. Increased catabolism of NAD(H) during protein ribosylation in the DNA damage repair process may explain the greater susceptibility of the elderly population to the acute respiratory symptoms of COVID-19. The molecular modelling studies proposed herein agree with this hypothesis
Identification of biological targets through the correlation between cell line chemosensitivity and protein expression pattern
No full textMatching biological data sequences is one of the most interesting ways to discover new bioactive compounds. In particular, matching cell chemosensitivity with a protein expression profile can be a useful approach to predict the activity of compounds against definite biological targets. In this review, we discuss this correlation. First, we analyze case studies in which some known drugs, acting on known targets, show a good correlation between their antiproliferative activities and protein expression when a large panel of tumor cells is considered. Then, we highlight how the application of in silico methods based on the correlation between cell line chemosensitivity and gene/protein expression patterns might be a quick, cheap, and interesting approach to predict the biological activity of investigated molecules
Bioisosteric heterocyclic analogues of natural bioactive flavonoids by scaffold-hopping approaches: State-of-the-art and perspectives in medicinal chemistry
Full text linkThe flavonoid family is a set of well-known bioactive natural molecules, with a wide range of potential therapeutic applications. Despite the promising results obtained in preliminary in vitro/vivo studies, their pharmacokinetic and pharmacodynamic profiles are severely compromised by chemical instability. To address this issue, the scaffold-hopping approach is a promising strategy for the structural optimization of natural leads to discover more potent analogues. In this scenario, this Perspective provides a critical analysis on how the replacement of the chromon-4-one flavonoid core with other bioisosteric nitrogen/sulphur heterocycles might affect the chemical, pharmaceutical and biological properties of the resulting new chemical entities. The investigated derivatives were classified on the basis of their biological activity and potential therapeutic indications. For each session, the target(s), the specific mechanism of action, if available, and the key pharmacophoric moieties were highlighted, as revealed by X-ray crystal structures and in silico structure-based studies. Biological activity data, in vitro/vivo studies, were examined: a particular focus was given on the improvements observed with the new heterocyclic analogues compared to the natural flavonoids. This overview of the scaffold-hopping advantages in flavonoid compounds is of great interest to the medicinal chemistry community to better exploit the vast potential of these natural molecules and to identify new bioactive molecules
Innovative In Silico Method for Discovering Multi-Target JAK/STAT Inhibitors as Potential Anticancer Therapies
No full textThe JAK/STAT signaling pathway regulates key cellular processes such as immune modulation, cellular proliferation, and apoptosis. Its dysregulation is implicated in various cancers, making it an attractive target for anticancer therapies1. In this study, we present an innovative in silico strategy to identify multi-target inhibitors of JAK2, JAK3, and STAT3, key proteins in the JAK/STAT pathway, aimed at cancer treatment. We first refined the National Cancer Institute (NCI) database, consisting of 40,000 compounds, using QikProp and SwissADME to select drug-like candidates2. The Biotarget Predictor Tool (BPT), developed by our research group and available on the DRUDIT platform3, was then used in ON/OFF-target mode to predict compounds with high affinity for JAK2, JAK3, and STAT3, while minimizing off-target interactions with TNF-α and p53.
Next, a two-step Docking Virtual Screening Workflow was applied, consisting of Extra Precision (XP) Docking and Induced Fit Docking (IFD), to refine the top candidates. Among them, compound 755435 (Figure 1) exhibited strong binding affinities and stable interactions with JAK2, JAK3, and STAT3, as confirmed by Molecular Dynamics Simulations and Interaction Maps with key active site residues. This multi-target approach, combined with OFF-target minimization, suggests that compound 755435 may offer a dual therapeutic advantage: enhancing efficacy in targeting multiple components of the JAK/STAT pathway while reducing the side effects associated with OFF-target interactions. Our results offer a promising foundation for the further optimization and preclinical evaluation of novel anticancer agents aimed at the JAK/STAT pathway
Design, Synthesis, and In Silico Insights of new 4‐Piperazinylquinolines as Antiproliferative Agents against NCI Renal Cancer Cell Lines
Full text link: In the search for new anticancer compounds, quinoline and piperazine moieties represent the most promising pharmacophoric fragments for the development of more effective drugs. A particularly interesting approach in medicinal chemistry is molecular hybridization, where different known components are integrated into a single chemical entity, resulting in hybrid molecules with enhanced biological activity. In this study, we have developed a new series of 4-(4-benzoylpiperazin-1-yl)-6-nitroquinoline-3-carbonitrile compounds (8 a-l), with potential anticancer effect, by combining the quinoline, the piperazinyl and the benzoylamino moieties. The rationalized compounds (8 a-l) were first evaluated in silico to assess the ADMET and drug-likeness profiles, synthesized using appropriate synthetic strategies and then tested in vitro under the National Cancer Institute DTP-NCI60 program. The entire series exhibited potent anticancer activity against the renal cell carcinoma (RCC) cell line UO-31, with compounds 8 c and 8 g effectively inhibiting cancer cell growth without excessive cytotoxic effects (growth percentages of -7 and -19, respectively). In silico induced fit docking (IFD) and molecular dynamics (MD) studies provided further insights into the putative mechanisms of action for both compounds, which were predicted to strongly bind key oncogenic proteins involved in RCC progression. The promising in vitro and in silico results herein presented provide a solid foundation for the development of a new series of small heterocyclic molecules with anticancer activity
Combinatorial chemistry-driven In silico design and computational evaluation of covalent peptidomimetic SARS-CoV-2 main protease inhibitors via structure-based virtual screening and multivariate analysis
Full text link: The COVID-19 pandemic has underscored the urgent need for specific pharmacological treatments beyond existing vaccines. One of the most attractive targets for antiviral therapies development is the SARS-CoV-2 Main Protease (MPRO), a key enzyme in viral life. The lack of MPRO human homologs and its conservation rate among coronaviruses make this enzyme strategically important. Considering its mechanism of action, the catalytic cysteine residue (Cys145) presents a prime target for covalent inhibition. Electrophilic warhead inhibitors, designed to react with this catalytic site, mimic the amide peptide bonds of the viral polyproteins, thereby facilitating their binding and subsequent inactivation of the enzyme. Their activity is further potentiated when incorporated into peptidomimetic structures. In silico approaches are gaining increasing importance in the search for effective COVID-19 treatments. In this view, this study focuses on developing an innovative in silico protocol for identifying anti-SARS-CoV-2 agents covalently targeting MPRO. To this purpose, a combinatorial library of 450 peptidomimetic compounds with aldehydic warheads was generated, refined to 388 compounds through docking studies, and further evaluated for covalent binding capabilities, revealing that compounds 9-14, 16, and 20 exhibited significantly higher affinities compared to known inhibitors, even during a 200 ns dynamics simulation, thus affirming the validity of the adopted design strategy. Furthermore, this work takes the advantages of our in-house ligand-based tool, the Biotarget Predictor Tool, available in DRUDIT, integrated with both structure-based techniques and, interestingly, multivariate statistical analysis
Pyrido[2’,3’:4,5]pyrrolo[2,1-d][1,2,3,5]tetrazine-4(3H)-ones, a new class of temozolomide heteroanalogues
No full textTwelve derivatives of new ring system pyrido[2’,3’:4,5]pyrrolo[2,1-d][1,2,3,5]tetrazine were prepared in good yields by reaction of 2-diazo-3-ethoxycarbonyl-pyrrolo[3,2-b]pyridine with alkyl- or aryl-isocyanates. Nine derivatives, screened by the National Cancer Institute (Bethesda, MD) for the in vitro one dose primary anticancer assay against a panel of about 60 human tumor cell lines, showed no significant activity
A novel in silico approach for identifying multi-target JAK/STAT inhibitors as anticancer agents
Full text linkApoptosis, or programmed cell death, plays a pivotal role in maintaining cellular homeostasis by eliminating damaged or surplus cells. Dysregulation of signaling pathways, such as JAK/STAT, is implicated in various diseases, rendering them attractive therapeutic targets for potential new anticancer drugs. Concurrently, it is imperative to preserve essential proteins like TNF-α and p53 to maintain normal cellular life/death balance. In light of these considerations, this study employs an innovative in silico hybrid and hierarchical virtual screening approach aimed at identifying JAK/STAT multi-target inhibitors as potential anticancer agents for several tumoral diseases. Initially, the Biotarget Predictor Tool is utilized in a combined ON/OFF-target/Multitarget mode using the extensive National Cancer Institute (NCI) database, previously filtered by ADME evaluation tools. Subsequently, Molecular Docking studies are conducted on JAK2, JAK3, and STAT3, facilitating the identification of the most promising compound, 755435. Finally, Molecular Dynamics Simulations validate the high stability of the potential multitarget inhibitor 755435 in complex with JAK2, JAK3, and STAT3
Pyrido[4′,3′:4,5]pyrrolo[2,1-d][1,2,3,5]tetrazines, a new class of Temozolomide heteroanalogues
No full textA series of derivatives of new ring system pyrido[4’,3’:4,5]pyrrolo[2,1-d] [1,2,3,5]tetrazine was
obtained from moderate to excellent yields by reaction of 2-diazo-3-ethoxycarbonyl-pyrrolo[2,3-
c]pyridine with alkyl- or aryl-isocyanates in dichlorometane at room temperature or at 50 °C
under microwave irradiation
- …
