90 research outputs found
Pharmacophore modelling as useful tool in the lead compounds identification and optimization
The goal of computer-aided molecular design methods in modern medicinal chemistry is to reduce
the overall cost and time associated to the discovery and development of a new drug by identifying
the most promising candidates to focus the experimental efforts on. Very often, many drug
discovery projects have reached already a well-advanced stage before detailed structural data on the
protein target have become available. A possible consequence is that often, medicinal chemists
develop novel compounds for a target using preliminary structure–activity information, together
with the theoretical models of interactions. Only responses that are consistent with the working
hypothesis contribute to an evolution of the used models. Within this framework, the
pharmacophore approach has proven to be successful, allowing the perception and understanding of
key interactions between a receptor and a ligand[1]. In recent years, our research group exploited
this useful modeling tool with the aim to identify new chemical entities and/or optimizing known
lead compounds to obtain more active drugs in the field of antitumor, antiviral, and antibacterial
drugs. In this communication, we present an overview of our recent works in which we used the
pharmacophore modelling approach combined with induced fit docking, 3D-QSAR approach, and
HTVS for the analysis of drug-receptor interactions and the discovery of new inhibitors of IKKβ,
Bcl-xl, and c-kit tyrosine kinase, all targets involved into the initiation and the development of
different types of cancer[2-5]
DRUDIT: web-based DRUgs DIscovery Tools to design small molecules as modulators of biological targets.
Abstract
Motivation
New in silico tools to predict biological affinities for input structures are presented. The tools are implemented in the DRUDIT (DRUgs DIscovery Tools) web service. The DRUDIT biological finder module is based on molecular descriptors that are calculated by the MOLDESTO (MOLecular DEScriptors TOol) software module developed by the same authors, which is able to calculate more than one thousand molecular descriptors. At this stage, DRUDIT includes 250 biological targets, but new external targets can be added. This feature extends the application scope of DRUDIT to several fields. Moreover, two more functions are implemented: the multi- and on/off-target tasks. These tools applied to input structures allow for predicting the polypharmacology and evaluating the collateral effects.
Results
The applications described in the article show that DRUDIT is able to predict a single biological target, to identify similarities among biological targets, and to discriminate different target isoforms. The main advantages of DRUDIT for the scientific community lie in its ease of use by worldwide scientists and the possibility to be used also without specific, and often expensive, hardware and software. In fact, it is fully accessible through the WWW from any device to perform calculations. Just a click or a tap can start tasks to predict biological properties for new compounds or repurpose drugs, lead compounds, or unsuccessful compounds. To date, DRUDIT is supported by four servers each able to execute 8 jobs simultaneously.
Availability and implementation
The web service is accessible at the www.drudit.com URL and its use is free of charge.
Supplementary information
Supplementary data are available at Bioinformatics online
In Silico Design of New Dual Inhibitors of SARS-CoV-2 MPRO through Ligand- and Structure-Based Methods
The viral main protease is one of the most attractive targets among all key enzymes involved in the life cycle of SARS-CoV-2. Considering its mechanism of action, both the catalytic and dimerization regions could represent crucial sites for modulating its activity. Dual-binding the SARS-CoV-2 main protease inhibitors could arrest the replication process of the virus by simultaneously preventing dimerization and proteolytic activity. To this aim, in the present work, we identified two series' of small molecules with a significant affinity for SARS-CoV-2 M-PRO, by a hybrid virtual screening protocol, combining ligand- and structure-based approaches with multivariate statistical analysis. The Biotarget Predictor Tool was used to filter a large in-house structural database and select a set of benzo[b]thiophene and benzo[b]furan derivatives. ADME properties were investigated, and induced fit docking studies were performed to confirm the DRUDIT prediction. Principal component analysis and docking protocol at the SARS-CoV-2 M-PRO dimerization site enable the identification of compounds 1b,c,i,l and 2i,l as promising drug molecules, showing favorable dual binding site affinity on SARS-CoV-2 M-PRO
Nanostructured Lipid Carriers-Containing Anticancer Compounds: Preparation, Characterization, and Cytotoxicity Studies
This article describes the development of nanostructured lipid carriers (NLC) as colloidal carriers for two antitumor compounds that possess a remarkable antineoplastic activity. But their limited stability and low solubility in water could give a very low parenteral bioavailability. Results revealed an enhancement of the cytotoxicity effect of drug-loaded NLC on human prostate cancer (PC-3) and human hepatocellular carcinoma (HuH-6, HuH-7) cell lines with respect to that of both free drugs. Results of characterization studies strongly support the potential application of these drugs-loaded NLC as prolonged delivery systems for lipophilic drugs by several administration routes, in particular for intravenous administration
Design and Synthesis of Novel Thieno[3,2-c]quinoline Compounds with Antiproliferative Activity on RET-Dependent Medullary Thyroid Cancer Cells
RET kinase gain-of-function mutations represent the main cause of the high aggressiveness and invasiveness of medullary thyroid cancer (MTC). The selective inhibition of the RET kinase is a suitable strategy for the treatment of this endocrine neoplasia. Herein, we performed an innovative ligand-based virtual screening protocol using the DRUDITonline web service, focusing on the RET kinase as a biological target. In this process, thieno[3,2-c]quinolines 6a-e and 7a-e were proposed as new potential RET inhibitors. The selected compounds were synthetized by appropriate synthetic strategies, and in vitro evaluation of antiproliferative properties conducted on the particularly aggressive MTC cell line TT(C634R) identified compounds 6a-d as promising anticancer agents, with IC50 values in the micromolar range. Further structure-based computational studies revealed a significant capability of the most active compounds to the complex RET tyrosine kinase domain. The interesting antiproliferative results supported by in silico predictions suggest that these compounds may represent a starting point for the development of a new series of small heterocyclic molecules for the treatment of MTC
Giant elephantiasis neuromatosa in the setting of neurofibromatosis type 1: A case report
Elephantiasis neuromatosa (EN) can arise from a plexiform neurofibroma of the superficial and deep nerves developing from a hyperproliferation of the perineural connective tissue infiltrating adjacent fat and muscles. To date, the clinical association between EN and neurofibromatosis type 1 (NF1) has been poorly defined, particularly with regard to the role of lymphatic alterations and the consequent lymphedema. The present study reports the clinical and biomolecular features of EN in a NF1 patient with the clear clinical diagnostic criteria of multiple caf\ue8-au-lait macules, neurofibromas, EN, a positive family history and a novel NF1 germline c.1541_1542del mutation. Lymphoscintigraphy (LS) highlighted marked dermal backflow in the affected limb, hypertrophy of the ipsilateral inguinal and external iliac lymph nodes, and a bilateral lower limb lymph flow delay. These data support the hypothesis that an extensive hyperproliferative process involving perineural connective, limb soft tissues, bones and the lymphatic system can be responsible for EN in NF1 patients, on the basis of adipocyte metaplasia triggered by lymphostasis and lymphedema, and bone overgrowth and gigantism caused by chronic hyperemia. LS and magnetic resonance imaging can be efficacious tools in the diagnosis and clinical characterization of the early onset of the disease
Design and synthesis of high affinity compounds for the Hsp60 expression control in carcinogenic processes
First observed in cells exposed to high temperatures, Heat shock proteins (Hsps) are
nowadays considered the most important cell “chaperone” complexes over-Âexpressed
in response to a number of cell stress stimuli.1 The chaperone activity is the main
function of the eukaryotic Heat shock protein 60 kDa (Hsp60), involved in the capture
and refold of unfolded or misfolded proteins. Additional roles in signal transduction,2
senescence activation3 and apoptosis4 have been ascribed to cytosolic Hsp60. During
the carcinogenIc process, in vivo studies demonstrated increased levels of human
Hsp60 in several organs, such as uterine exocervix,5 large bowel,6 and prostate.6
In this context, our study aims to elucidate the structural details of the interaction
between Hsp60 and novel designed antagonists able to specifically block this
chaperonine. A preliminary virtual screening of 24 million molecules, available in the
Zinc database, was carried out on the ATP-Âbinding site of a bacterial Hsp60 monomer,
the coordinates of which were taken from Protein Data Bank (ID: 1WE3), figure 1.
Compounds with high affinity were further refined by other in silico protocols previously
and successfully applied by us in the study of several biological targets.7The analysis of virtual screening results highlights the N-Â{5-Â[1H-Âimidazol-Â4-Âyl-Âmethyl)-Â
amino]-Âbenzofuran-Â3-Âyl}-Âbenzamides of type 1 as interesting series for the inhibition of
Hsp60 ATP-Âbinding site. Selected compounds were prepared in excellent yields,
following appropriate synthetic pathways. All compounds are currently tested in order
to proof they potential anticancer activity as modulator of Hsp60 function in tumor cells
NF1 truncating mutations associated to aggressive clinical phenotype with elephantiasis neuromatosa and solid malignancies
Background/aim: Von Recklinghausen disease is a syndrome characterized by a wide phenotypic variability giving rise to both, cutaneous and visceral benign and malignant neoplasms. The first include cutaneous neurofibromas, subcutaneous and plexiform neurofibromas. The latter can undergo malignant transformation and/or determine elephantiasis neuromatosa. Visceral tumors may include malignant peripheral nerve sheet tumors, gastrointestinal stromal tumors, cerebral gliomas and abdominal neurofibromas. In the present study, the authors discuss the clinical and biomolecular characterization of a cohort of 20 families with a diagnosis of type 1 neurofibromatosis. Patients and methods: Clinically, the cohort includes three probands with elephantiasis neuromatosa and a peculiarly high incidence of breast and gastrointestinal cancer. Results: Among the 14 NF1 mutations documented, 10 encoding for a truncated protein have been associated to particularly aggressive clinical phenotypes including elephantiasis neuromatosa, malignant peripheral nerve sheet tumors, breast cancer, gastrointestinal stromal tumors. Conclusion: This effect on protein synthesis, rather than the type of NF1 mutation, is the key to the explanation of the genotype-phenotype correlations in the context of neurofibromatosis type 1
Dye-Derived Red-Emitting Carbon Dots for Lasing and Solid-State Lighting
Carbon dots are carbon-based nanoparticles renowned for their intense light-emitting capabilities covering the whole visible light range. Achieving carbon dots emitting in the red region with high efficiency is extremely relevant due to their huge potential in biological applications and in optoelectronics. Currently, photoluminescence in such an energy interval is often associated with polyheterocyclic molecular domains forming during the synthesis that, however, present low emission efficiency and issues in controlling the optical features. Here, we overcome these problems by solvothermally synthesizing carbon dots starting from Neutral Red, a common red-emitting dye, as a molecular precursor. As a result of the synthesis, such molecular fluorophore is incorporated into a carbonaceous core while retaining its original optical properties. The obtained nanoparticles are highly luminescent in the red region, with a quantum yield comparable to that of the starting dye. Most importantly, the nanoparticle carbogenic matrix protects the Neutral Red molecules from photobleaching under ultraviolet excitation while preventing aggregation-induced quenching, thus allowing solid-state emission. These advantages have been exploited to develop a fluorescence-based color conversion layer by fabricating polymer-based highly concentrated solid-state carbon dot nanocomposites. Finally, the dye-based carbon dots demonstrate both stable Fabry-Perot lasing and efficient random lasing emission in the red region
Antiproliferative Activity Predictor: un nuovo tool in silico per predire l’attività antiproliferativa nei confronti del pannello NCI60
- …