A5048810189- Biochemical and Molecular Research
- Colorectal Cancer Treatments and Studies
- Trypanosoma species research and implications
- Synthesis and Biological Evaluation
- Cancer therapeutics and mechanisms
- Research on Leishmaniasis Studies
- Enzyme Structure and Function
- Synthesis and biological activity
- Tuberculosis Research and Epidemiology
- Cancer, Hypoxia, and Metabolism
- Meat and Animal Product Quality
- Cancer Research and Treatments
- Computational Drug Discovery Methods
- Biosensors and Analytical Detection
- Antibiotics Pharmacokinetics and Efficacy
- Cancer Treatment and Pharmacology
- Click Chemistry and Applications
- Folate and B Vitamins Research
- Pneumocystis jirovecii pneumonia detection and treatment
- Cancer-related Molecular Pathways
- Food Quality and Safety Studies
- Advanced biosensing and bioanalysis techniques
- HIV/AIDS drug development and treatment
- Phytochemical compounds biological activities
- Chemical synthesis and pharmacological studies
University of Modena and Reggio Emilia
2015-2025
Excel Life Sciences (India)
2017-2022
Gdańsk Medical University
2022
Aboca (Italy)
2022
University of Verona
2022
Quantitative BioSciences
2017
Tydock Pharma (Italy)
2017
University of Münster
2010
The expression of acid ceramidase (AC) – a cysteine amidase that hydrolyses the proapoptotic lipid ceramide is abnormally high in several human tumors, which suggestive role chemoresistance. Available AC inhibitors lack, however, potency and drug-likeness necessary to test this idea. Here we show antineoplastic drug carmofur, used clinic treat colorectal cancers, potent inhibitor property essential its anti-proliferative effects. Modifications chemical scaffold carmofur yield new act...
Phenotypic screening of a quinoxaline library against replicating Mycobacterium tuberculosis led to the identification lead compound Ty38c (3-((4-methoxybenzyl)amino)-6-(trifluoromethyl)quinoxaline-2-carboxylic acid). With an MIC99 and MBC 3.1 μM, is bactericidal active intracellular bacteria. To investigate its mechanism action, we isolated mutants resistant sequenced their genomes. Mutations were found in rv3405c, coding for transcriptional repressor divergently expressed rv3406 gene....
Human thymidylate synthase is a homodimeric enzyme that plays key role in DNA synthesis and target for several clinically important anticancer drugs bind to its active site. We have designed peptides specifically dimer interface. Here we show through X-ray diffraction, spectroscopic, kinetic, calorimetric evidence the do indeed at interface of dimeric protein stabilize di-inactive form. The "LR" peptide binds previously unknown binding site shows undescribed mechanism allosteric inhibition...
Folate analogue inhibitors of Leishmania major pteridine reductase (PTR1) are potential antiparasitic drug candidates for combined therapy with dihydrofolate (DHFR) inhibitors. To identify new molecules specificity PTR1, we carried out a virtual screening the Available Chemicals Directory (ACD) database to select compounds that could interact L. PTR1 but not human DHFR. Through two rounds discovery, successfully identified eighteen drug-like low micromolar affinities and high in vitro...
Flavonoids represent a potential source of new antitrypanosomatidic leads. Starting from library natural products, we combined target-based screening on pteridine reductase 1 with phenotypic Trypanosoma brucei for hit identification. Flavonols were identified as hits, and 16 derivatives was synthesized. Twelve compounds showed EC50 values against T. below 10 μM. Four X-ray crystal structures docking studies explained the observed structure–activity relationships. Compound 2...
The upregulation of pteridine reductase (PTR1) is a major contributor to antifolate drug resistance in Leishmania spp., as it provides salvage pathway that bypasses dihydrofolate (DHFR) inhibition. structure-based optimization the PTR1 inhibitor methyl-1-[4-(2,4-diaminopteridin-6-ylmethylamino)benzoyl]piperidine-4-carboxylate (1) led synthesis focused compound library which showed significantly improved selectivity for parasite's folate-dependent enzyme. When used combination with...
2-Amino-benzo[d]thiazole was identified as a new scaffold for the development of improved pteridine reductase-1 (PTR1) inhibitors and anti-trypanosomatidic agents. Molecular docking crystallography guided design synthesis 42 benzothiazoles. The compounds were assessed Trypanosoma brucei Leishmania major PTR1 inhibition in vitro activity against T. amastigote infantum. We several 2-amino-benzo[d]thiazoles with enzymatic (TbPTR1 IC50 = 0.35 μM; LmPTR1 1.9 μM) low μM antiparasitic brucei. ten...
Pteridine reductase 1 (PTR1) is a key folate pathway enzyme of pathogenic trypanosomatids that reduces biopterin to dihydro- and tetrahydrobiopterin. It promising target for drug design against diseases such as sleeping sickness or leishmaniases. Amongst known PTR1 inhibitors, 2-aminobenzothiazole derivatives the pocket were previously found show good overall toxicity profiles some them display anti-parasite activity. On other hand, compounds containing 3,4-dichlorophenyl moiety,...
Drug resistance to therapeutic antibiotics poses a challenge the identification of novel targets and drugs for treatment infectious diseases. Infections caused by Enterococcus faecalis are major health problem. Thymidylate synthase (TS) from E. is potential target antibacterial therapy. The X-ray crystallographic structure thymidylate (EfTS), which was obtained as native binary complex composed EfTS 5-formyltetrahydrofolate (5-FTHF), has been determined. provides evidence that...
Pteridine reductase-1 (PTR1) is a promising drug target for the treatment of trypanosomiasis. We investigated potential previously identified class thiadiazole inhibitors Leishmania major PTR1 activity against Trypanosoma brucei (Tb). solved crystal structures several TbPTR1-inhibitor complexes to guide structure-based design new derivatives. Subsequent synthesis and enzyme- cell-based assays confirm new, mid-micromolar TbPTR1 with low toxicity. In particular, compound 4m,...
Thymidylate synthase (TS) is an enzyme of paramount importance as it provides the only de novo source deoxy-thymidine monophosphate (dTMP). dTMP, essential for DNA synthesis, produced by TS-catalyzed reductive methylation 2'-deoxyuridine-5'-monophosphate (dUMP) using N⁵,N10-methylenetetrahydrofolate (mTHF) a cofactor. TS ubiquitous and validated drug target. enzymes from different organisms differ in sequence structure, but are all obligate homodimers. The structural mechanistic differences...
The optimization of compounds with multiple targets is a difficult multidimensional problem in the drug discovery cycle. Here, we present systematic, multidisciplinary approach to development selective antiparasitic compounds. Computational fragment-based design novel pteridine derivatives along iterations crystallographic structure determination allowed for derivation structure–activity relationship multitarget inhibition. yielded showing apparent picomolar inhibition T. brucei reductase 1...
Human thymidylate synthase (hTS) was targeted through a virtual screening approach. The most optimal inhibitor identified, 2-{4-hydroxy-2-[(2-hydroxybenzylidene)hydrazono]-2,5-dihydrothiazol-5-yl}-N-(3-trifluoromethylphenyl)acetamide (5), showed mixed-type inhibition pattern, with K(i) of 1.3 μM and activity against ovarian cancer cell lines the same potency as cisplatin. X-ray studies revealed that it binds inactive enzyme conformation. This study is first example nonpeptidic hTS exhibits...
Thymidylate synthase (TS) is a target for pemetrexed and the prodrug 5-fluorouracil (5-FU) that inhibit protein by binding at its active site. Prolonged administration of these drugs causes TS overexpression, leading to drug resistance. The peptide lead, LR (LSCQLYQR), allosterically stabilizes inactive form inhibits ovarian cancer (OC) cell growth with stable decreased dihydrofolate reductase (DHFR) expression. To improve inhibition anticancer effect, we have developed 35 peptides modifying...
Abstract Repurposing and repositioning drugs has become a frequently pursued successful strategy in the current era, as new chemical entities are increasingly difficult to find get approved. Herein we report an integrated BioGPS/FLAPdock pipeline for rapid effective off‐target identification drug repurposing. Our method is based on structural properties of protein binding sites, that is, ligand image, encoded GRID molecular interaction fields (MIFs). Protein similarity disclosed through...
Thymidylate synthase X (ThyX) represents an attractive target for tuberculosis drug discovery. Herein, we selected 16 compounds through a virtual screening approach. We solved the first X-ray crystal structure of Thermatoga maritima (Tm) ThyX in complex with nonsubstrate analog inhibitor. Given active site similarities between Mycobacterium (Mtb-ThyX) and Tm-ThyX, our paves way structure-based design novel antimycobacterial compounds. The 1H-imidazo[4,5-d]pyridazine was identified as...
Broad-spectrum anti-infective chemotherapy agents with activity against Trypanosomes, Leishmania, and Mycobacterium tuberculosis species were identified from a high-throughput phenotypic screening program of the 456 compounds belonging to Ty-Box, an in-house industry database. Compound characterization using machine learning approaches enabled identification synthesis 44 broad-spectrum antiparasitic minimal toxicity Trypanosoma brucei, Leishmania Infantum, cruzi. In vitro studies confirmed...
To identify specific bacterial thymidylate synthase (TS) inhibitors, we exploited phenolphthalein (PTH), which inhibits both and human enzymes. The X-ray crystal structure of Lactobacillus casei TS (LcTS) that binds PTH showed multiple binding modes the inhibitor, prevented a classical structure-based drug design approach. overcome this issue, synthesized two phthalimidic libraries were tested against enzymes then performed crystallographic screening active compounds. Compounds 6A, 8A, 12A...