Co-development of a school-based and primary care-based multicomponent intervention to improve HPV vaccine coverage amongst French adolescents (the PrevHPV Study).

INTRODUCTION: Despite various efforts to improve human papillomavirus (HPV) vaccine coverage in France, it has always been lower than in most other high-income countries. The health authorities launched in 2018 the national PrevHPV research programme to (1) co-develop with stakeholders and (2) evaluate the impact of a multicomponent complex intervention aimed at improving HPV vaccine coverage amongst French adolescents. OBJECTIVE: To describe the development process of the PrevHPV intervention using the GUIDance for rEporting of intervention Development framework as a guide. METHODS: To develop the intervention, we used findings from (1) published evidence on effective strategies to improve vaccination uptake and on theoretical frameworks of health behaviour change; (2) primary data on target populations' knowledge, beliefs, attitudes, preferences, behaviours and practices as well as the facilitators and barriers to HPV vaccination collected as part of the PrevHPV Programme and (3) the advice of working groups involving stakeholders in a participatory approach. We paid attention to developing an intervention that would maximise reach, adoption, implementation and maintenance in real-world contexts. RESULTS: We co-developed three components: (1) adolescents' and parents' education and motivation using eHealth tools (web conferences, videos, and a serious video game) and participatory learning at school; (2) general practitioners' e-learning training on HPV using motivational interviewing techniques and provision of a decision aid tool and (3) easier access to vaccination through vaccination days organised on participating middle schools' premises to propose free of charge initiation of the HPV vaccination. CONCLUSION: We co-developed a multicomponent intervention that addresses a range of barriers and enablers of HPV vaccination. The next step is to build on the results of its evaluation to refine it before scaling it up if proven efficient. If so, it will add to the small number of multicomponent interventions aimed at improving HPV vaccination worldwide. PATIENT OR PUBLIC CONTRIBUTION: The public (adolescents, their parents, school staff and health professionals) participated in the needs assessment using a mixed methods approach. The public was also involved in the components' development process to generate ideas about potential activities/tools, critically revise the successive versions of the tools and provide advice about the intervention practicalities, feasibility and maintenance.

Synthesis of 1,3,4-Thiadiazole Derivatives and Their Anticancer Evaluation.

Thiadiazole derivatives have garnered significant attention in the field of medicinal chemistry due to their diverse pharmacological activities, including anticancer properties. This article presents the synthesis of a series of thiadiazole derivatives and investigates their chemical characterization and potential anticancer effects on various cell lines. The results of the nuclear magnetic resonance (NMR) analyses confirmed the successful formation of the target compounds. The anticancer potential was evaluated through in silico and in vitro cell-based assays using LoVo and MCF-7 cancer lines. The assays included cell viability, proliferation, apoptosis, and cell cycle analysis to assess the compounds' effects on cancer cell growth and survival. Daphnia magna was used as an invertebrate model for the toxicity evaluation of the compounds. The results revealed promising anticancer activity for several of the synthesized derivatives, suggesting their potential as lead compounds for further drug development. The novel compound 2g, 5-[2-(benzenesulfonylmethyl)phenyl]-1,3,4-thiadiazol-2-amine, demonstrated good anti-proliferative effects, exhibiting an IC50 value of 2.44 µM against LoVo and 23.29 µM against MCF-7 after a 48-h incubation and little toxic effects in the Daphnia test.

Interaction of Some Asymmetrical Porphyrins with U937 Cell Membranes-In Vitro and In Silico Studies.

The aim of the present study was to assess the effects exerted in vitro by three asymmetrical porphyrins (5-(2-hydroxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrin, 5-(2-hydroxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrinatozinc(II), and 5-(2-hydroxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl)porphyrinatocopper(II)) on the transmembrane potential and the membrane anisotropy of U937 cell lines, using bis-(1,3-dibutylbarbituric acid)trimethine oxonol (DiBAC4(3)) and 1-(4-trimethylammoniumphenyl)-6-phenyl-1,3,5-hexatriene p-toluenesulfonate (TMA-DPH), respectively, as fluorescent probes for fluorescence spectrophotometry. The results indicate the hyperpolarizing effect of porphyrins in the concentration range of 0.5, 5, and 50 µM on the membrane of human U937 monocytic cells. Moreover, the tested porphyrins were shown to increase membrane anisotropy. Altogether, the results evidence the interaction of asymmetrical porphyrins with the membrane of U937 cells, with potential consequences on cellular homeostasis. Molecular docking simulations, and Molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) free energy of binding calculations, supported the hypothesis that the investigated porphyrinic compounds could potentially bind to membrane proteins, with a critical role in regulating the transmembrane potential. Thus, both the free base porphyrins and the metalloporphyrins could bind to the SERCA2b (sarco/endoplasmic reticulum ATPase isoform 2b) calcium pump, while the metal complexes may specifically interact and modulate calcium-dependent (large conductance calcium-activated potassium channel, Slo1/KCa1.1), and ATP-sensitive (KATP), potassium channels. Further studies are required to investigate these interactions and their impact on cellular homeostasis and functionality.

Porphyrin Macrocycles: General Properties and Theranostic Potential.

Despite specialists' efforts to find the best solutions for cancer diagnosis and therapy, this pathology remains the biggest health threat in the world. Global statistics concerning deaths associated with cancer are alarming; therefore, it is necessary to intensify interdisciplinary research in order to identify efficient strategies for cancer diagnosis and therapy, by using new molecules with optimal therapeutic potential and minimal adverse effects. This review focuses on studies of porphyrin macrocycles with regard to their structural and spectral profiles relevant to their applicability in efficient cancer diagnosis and therapy. Furthermore, we present a critical overview of the main commercial formulations, followed by short descriptions of some strategies approached in the development of third-generation photosensitizers.

The Importance of the Pyrazole Scaffold in the Design of Protein Kinases Inhibitors as Targeted Anticancer Therapies.

The altered activation or overexpression of protein kinases (PKs) is a major subject of research in oncology and their inhibition using small molecules, protein kinases inhibitors (PKI) is the best available option for the cure of cancer. The pyrazole ring is extensively employed in the field of medicinal chemistry and drug development strategies, playing a vital role as a fundamental framework in the structure of various PKIs. This scaffold holds major importance and is considered a privileged structure based on its synthetic accessibility, drug-like properties, and its versatile bioisosteric replacement function. It has proven to play a key role in many PKI, such as the inhibitors of Akt, Aurora kinases, MAPK, B-raf, JAK, Bcr-Abl, c-Met, PDGFR, FGFRT, and RET. Of the 74 small molecule PKI approved by the US FDA, 8 contain a pyrazole ring: Avapritinib, Asciminib, Crizotinib, Encorafenib, Erdafitinib, Pralsetinib, Pirtobrutinib, and Ruxolitinib. The focus of this review is on the importance of the unfused pyrazole ring within the clinically tested PKI and on the additional required elements of their chemical structures. Related important pyrazole fused scaffolds like indazole, pyrrolo[1,2-b]pyrazole, pyrazolo[4,3-b]pyridine, pyrazolo[1,5-a]pyrimidine, or pyrazolo[3,4-d]pyrimidine are beyond the subject of this work.

Effects of Venlafaxine, Risperidone and Febuxostat on Cuprizone-Induced Demyelination, Behavioral Deficits and Oxidative Stress.

Multiple sclerosis (MS) is a demyelinating, autoimmune disease that affects a large number of young adults. Novel therapies for MS are needed considering the efficiency and safety limitations of current treatments. In our study, we investigated the effects of venlafaxine (antidepressant, serotonin-norepinephrine reuptake inhibitor), risperidone (atypical antipsychotic) and febuxostat (gout medication, xanthine oxidase inhibitor) in the cuprizone mouse model of acute demyelination, hypothesizing an antagonistic effect on TRPA1 calcium channels. Cuprizone and drugs were administered to C57BL6/J mice for five weeks and locomotor activity, motor performance and cold sensitivity were assessed. Mice brains were harvested for histological staining and assessment of oxidative stress markers. Febuxostat and metabolites of venlafaxine (desvenlafaxine) and risperidone (paliperidone) were tested for TRPA1 antagonistic activity. Following treatment, venlafaxine and risperidone significantly improved motor performance and sensitivity to a cold stimulus. All administered drugs ameliorated the cuprizone-induced deficit of superoxide dismutase activity. Desvenlafaxine and paliperidone showed no activity on TRPA1, while febuxostat exhibited agonistic activity at high concentrations. Our findings indicated that all three drugs offered some protection against the effects of cuprizone-induced demyelination. The agonistic activity of febuxostat can be of potential use for discovering novel TRPA1 ligands.

Targeting Monoacylglycerol Lipase in Pursuit of Therapies for Neurological and Neurodegenerative Diseases.

Neurological and neurodegenerative diseases are debilitating conditions, and frequently lack an effective treatment. Monoacylglycerol lipase (MAGL) is a key enzyme involved in the metabolism of 2-AG (2-arachidonoylglycerol), a neuroprotective endocannabinoid intimately linked to the generation of pro- and anti-inflammatory molecules. Consequently, synthesizing selective MAGL inhibitors has become a focus point in drug design and development. The purpose of this review was to summarize the diverse synthetic scaffolds of MAGL inhibitors concerning their potency, mechanisms of action and potential therapeutic applications, focusing on the results of studies published in the past five years. The main irreversible inhibitors identified were derivatives of hexafluoroisopropyl alcohol carbamates, glycol carbamates, azetidone triazole ureas and benzisothiazolinone, whereas the most promising reversible inhibitors were derivatives of salicylketoxime, piperidine, pyrrolidone and azetidinyl amides. We reviewed the results of in-depth chemical, mechanistic and computational studies on MAGL inhibitors, in addition to the results of in vitro findings concerning selectivity and potency of inhibitors, using the half maximal inhibitory concentration (IC50) as an indicator of their effect on MAGL. Further, for highlighting the potential usefulness of highly selective and effective inhibitors, we examined the preclinical in vivo reports regarding the promising therapeutic applications of MAGL pharmacological inhibition.

Molecular Docking and Screening Studies of New Natural Sortase A Inhibitors.

To date, multi-drug resistant bacteria represent an increasing health threat, with a high impact on mortality, morbidity, and health costs on a global scale. The ability of bacteria to rapidly and permanently acquire new virulence factors and drug-resistance elements requires the development of new antimicrobial agents and selection of new proper targets, such as sortase A. This specific bacterial target plays an important role in the virulence of many Gram-positive pathogens, and its inhibition should produce a mild evolutionary pressure which will not favor the development of resistance. A primary screening using a fluorescence resonance energy transfer assay was used to experimentally evaluate the inhibitory activity of several compounds on sortase A. Using molecular docking and structure-activity relationship analyses, several lead inhibitors were identified, which were further tested for antimicrobial activity using the well diffusion test and minimum inhibitory concentration. The toxicity was assessed using the Daphnia magna test and used as a future screening filter. Three natural compounds were identified in this study as promising candidates for further development into therapeutically useful anti-infective agents that could be used to treat infections caused by multi-drug resistant bacterial pathogens which include sortase A in their enzymatic set.

Transient Receptor Potential Ankyrin 1 (TRPA1) Modulation by 4-Hydroxynonenal (4-HNE) in Pancreatic Adenocarcinoma Cell Lines: Putative Roles for Therapies.

BACKGROUND: Transient receptor potential channels (TRP) are overexpressed in some pancreatic adenocarcinoma (PDAC) patients and cell lines, settling them as putative therapeutic targets in this disease. Reactive oxygen species (ROS), with levels increased in PDAC, modulate some members of the TRP family renamed "redox channels". Here, we investigate the direct effects of 4-hydroxinonenal (4-HNE) on TRPA1, natively expressed in PDAC cell lines and in association with cell migration and cell cycle progression. METHODS: We performed microfluorimetry experiments, while the activation of resident membrane channels was investigated using confocal microscopy. We applied a prospective molecular docking of 4-HNE using Autodock and AutoDock Tools4. Also, we simulated the diffusion of 4-HNE through the membrane from the extracellular space with the Permeability of Molecules across Membranes (PerMM) web server. The analysis of cell migration was performed using the wound healing assay, and cell cycle progression was acquired using a Beckman Coulter CytoFlex flow cytometer. RESULTS: Our results show, for the first time in PDAC, that 4-HNE diffuses through the cell membrane and rapidly activates Ca2+ uptake in PDAC cells. This process depends on TRPA1 activation, as 4-HNE forms a covalent binding with a pocket-like region within the intracellular N-terminal of the channel, shaped by the cysteine residues 621, 641, and 665. The activation of TRPA1 by 4-HNE inhibits cell migration and induces cell cycle arrest in the G2/M phase. CONCLUSIONS: Our study brings new insights into the effects of 4-HNE, highlighting the activation of the TRPA1 channel, a druggable, putative target for PDAC-expressing tumors.

In Silico and In Vitro Studies on an Asymmetrical Porphyrin Derivative with Therapeutic Potential in Skin Disorders.

For developing novel photosensitizers with therapeutic potential in non-malignant and malignant cutaneous disorders, the unsymmetrical porphyrin, 5-(2-hydroxy-3-methoxyphenyl)-10, 15, 20-tris-(4-carboxymethylphenyl) porphyrin, was evaluated in silico and in vitro. The cellular uptake of the investigated porphyrin and its ability to perform photodynamic therapy were investigated in terms of the viability, proliferation, and necrosis of human HaCaT keratinocytes and human Hs27 skin fibroblasts, in correlation with the predictions regarding diffusion through cell membranes, ADMET profile (absorption, distribution, metabolism, elimination, toxicity), and potential pharmacological mechanism. Molecular docking and 250 ns molecular dynamics simulations revealed that P5.2 has the potential to form a relatively stable complex with the carbonic anhydrase IX catalytic site, the lowest predicted free energy of binding (MM/PBSA) being -39.097 kcal/mol. The results of the in vitro study showed that P5.2 is incorporated within 24 h in the investigated cells, especially in HaCaT keratinocytes, indicating its photosensitizing ability. Nevertheless, P5.2 does not exert significant cytotoxicity in "dark" conditions. In turn, PDT induced a decrease in the number of metabolically active HaCaT keratinocytes within 24 h, accompanied by a 4-fold increase in lactate dehydrogenase release, indicating its ability to perform PDT in human skin cells. The experimental results suggest that the asymmetrical porphyrin is a promising candidate theranostics agent for skin disorders.

Identification, analysis and prediction of valid and false information related to vaccines from Romanian tweets.

Introduction: The online misinformation might undermine the vaccination efforts. Therefore, given the fact that no study specifically analyzed online vaccine related content written in Romanian, the main objective of the study was to detect and evaluate tweets related to vaccines and written in Romanian language. Methods: 1,400 Romanian vaccine related tweets were manually classified in true, neutral and fake information and analyzed based on wordcloud representations, a correlation analysis between the three classes and specific tweet characteristics and the validation of several predictive machine learning algorithms. Results and discussion: The tweets annotated as misinformation showed specific word patterns and were liked and reshared more often as compared to the true and neutral ones. The validation of the machine learning algorithms yielded enhanced results in terms of Area Under the Receiver Operating Characteristic Curve Score (0.744-0.843) when evaluating the Support Vector Classifier. The predictive model estimates in a well calibrated manner the probability that a specific Twitter post is true, neutral or fake. The current study offers important insights regarding vaccine related online content written in an Eastern European language. Future studies must aim at building an online platform for rapid identification of vaccine misinformation and raising awareness for the general population.

Interpersonal Behaviors Questionnaire in Sport: Psychometric Analysis With Romanian Professional Athletes.

Building upon self-determination theory, our objective in this research was to adapt and analyze psychometrically the Interpersonal Behaviors Questionnaire (IBQ) in sport. Our participants were 642 professional athletes (55.14% men, Mage = 22.81) who completed an online survey measuring their perception of coaching behaviors, need satisfaction, need frustration, and motivation. The results showed a good fit for the 24-item IBQ with a six-factor correlated model (χ2/df = 4.178; CFI = .925; TLI = .912; SRMR = .048; RMSEA = .070), and we obtained evidence supporting its convergent and discriminant validity. The analyses also underpinned measurement invariance across gender, age, and sport, and confirmed good reliability. Criterion validity was met by positive associations of autonomy-supportive, competence-supportive, and relatedness-supportive behaviors with need satisfaction and autonomous motivation; and of autonomy-thwarting, competence-thwarting and relatedness-thwarting behaviors with need frustration, controlled motivation and amotivation. The adapted IBQ can be applied to the assessment of professional Romanian athletes' perceptions of need-supportive and need-thwarting coaching behaviors.

A PIM-1 Kinase Inhibitor Docking Optimization Study Based on Logistic Regression Models and Interaction Analysis.

PIM-1 kinase is a serine-threonine phosphorylating enzyme with implications in multiple types of malignancies, including prostate, breast, and blood cancers. Developing better search methodologies for PIM-1 kinase inhibitors may be a good strategy to speed up the discovery of an oncological drug approved for targeting this specific kinase. Computer-aided screening methods are promising approaches for the discovery of novel therapeutics, although certain limitations should be addressed. A frequent omission that is encountered in molecular docking is the lack of proper implementation of scoring functions and algorithms on the post-docking results, which usually alters the outcome of the virtual screening. The current study suggests a method for post-processing docking results, expressed either as binding affinity or score, that considers different binding modes of known inhibitors to the studied targets while making use of in vitro data, where available. The docking protocol successfully discriminated between known PIM-1 kinase inhibitors and decoy molecules, although binding energies alone were not sufficient to ensure a successful prediction. Logistic regression models were trained to predict the probability of PIM-1 kinase inhibitory activity based on binding energies and the presence of interactions with identified key amino acid residues. The selected model showed 80.9% true positive and 81.4% true negative rates. The discussed approach can be further applied in large-scale molecular docking campaigns to increase hit discovery success rates.

Resveratrol and Other Natural Oligomeric Stilbenoid Compounds and Their Therapeutic Applications.

The use of natural compounds as an alternative to synthetic molecules has become a significant subject of interest in recent decades. Stilbenoids are a group of phenolic compounds found in many plant species and they have recently gained the focus of a multitude of studies in medicine and chemistry, resveratrol being the most representative molecule. In this review, we focused on the research that illustrates the therapeutic potential of this class of natural molecules considering various diseases with higher incidence rates. PubChem database was searched for bioactivities of natural stilbenoids, while several keywords (i.e., "stilbenoids", "stilbenoid anticancer") were used to query PubMed database for relevant studies. The diversity and the simplicity of stilbenes' chemical structures together with the numerous biological sources are key elements that can simplify both the isolation of these compounds and the drug design of novel bioactive molecules. Resveratrol and other related compounds are heterogeneously distributed in plants and are mainly found in grapes and wine. Natural stilbenes were shown to possess a wide range of biological activities, such as antioxidant, anti-inflammatory, antihyperglycemic, cardioprotective, neuroprotective, and antineoplastic properties. While resveratrol is widely investigated for its benefits in various disorders, further studies are warranted to properly harness the therapeutic potential of less popular stilbenoid compounds.

Cetirizine and Levetiracetam as Inhibitors of Monoacylglycerol Lipase: Investigating Their Repurposing Potential as Novel Osteoarthritic Pain Therapies.

Osteoarthritis is characterized by progressive articular cartilage degradation, subchondral bone changes, and synovial inflammation, and affects various joints, causing pain and disability. Current osteoarthritis therapies, primarily focused on pain management, face limitations due to limited effectiveness and high risks of adverse effects. Safer and more effective treatments are urgently needed. Considering that the endocannabinoid 2-arachidonoyl glycerol is involved in pain processing, increasing its concentration through monoacylglycerol lipase (MAGL) inhibition reduces pain in various animal models. Furthermore, drug repurposing approaches leverage established drug safety profiles, presenting a cost-effective route to accelerate clinical application. To this end, cetirizine and levetiracetam were examined for their MAGL inhibitory effects. In vitro studies revealed that cetirizine and levetiracetam inhibited MAGL with IC50 values of 9.3931 µM and 3.0095 µM, respectively. In vivo experiments demonstrated that cetirizine, and to a lesser extent levetiracetam, reduced mechanical and thermal nociception in complete Freund adjuvant (CFA)-induced osteoarthritis in rats. Cetirizine exhibited a notable anti-inflammatory effect, reducing CFA-induced inflammation, as well as the inflammatory infiltrate and granuloma formation in the affected paw. These findings suggest that cetirizine may serve as a promising starting point for the development of novel compounds for osteoarthritis treatment, addressing both pain and inflammation.

Phytochemical Screening and Antioxidant Potential of Selected Extracts from Betula alba var. pendula Roth., Glycyrrhiza glabra L., and Avena sativa L.

The aim of the present study was to obtain, characterize, and evaluate the antioxidant potential of some extracts obtained from the bark of Betula alba var. pendula Roth., the root of Glycyrrhiza glabra L., and the green herb of the Avena sativa. The results revealed that the lowest IC50 value, determined by all three methods, was obtained for Betulae extractum (BE) (73.6 µg/mL-DPPH method, 11.2 µg/mL-ABTS method, and 58.7 µg/mL-FRAP method), followed by Liquiritiae extractum (LE) (805.6 µg/mL, 92.1 µg/mL, and 722 µg/mL) and Avenae extractum (1.13 mg/mL-DPPH method, 99.7 µg/mL-ABTS method, and 135.1 µg/mL-FRAP method). These results correlate with total polyphenols content (expressed in g tannic acid/100 g dry extract), with BE having more polyphenols than LE and AE (47.96 ± 9.7083 for BE, compared with 9.31 ± 0.9913 for LE and 40.55 ± 6.3715 for AE). The total flavonoid content (expressed as g rutoside/100 g dry extract) is similar for BE and LE (3.75 ± 0.3140 and 3.44 ± 0.3037) and smaller for AE (1.95 ± 0.0526). Therefore, Betulae extractum has the strongest antioxidant action, with an IC50 value very close to the standard used as a reference (ascorbic acid-16.5 µg/mL solution). The FT-ICR-MS analysis confirmed the presence of the major compounds in all three extracts. The antioxidant properties of the studied extracts were further supported by molecular docking experiments that revealed the potential of the analyzed phytochemicals to act as both noncovalent and covalent activators of the Nrf2 signaling pathway, with promising benefits in treating various skin disorders.

Assessment of Some Unsymmetrical Porphyrins as Promising Molecules for Photodynamic Therapy of Cutaneous Disorders.

In order to select for further development novel photosensitizers for photodynamic therapy in cutaneous disorders, three unsymmetrical porphyrins, namely 5-(4-hydroxy-3-methoxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl) porphyrin (P2.2), 5-(2-hydroxy-5-methoxyphenyl)-10,15,20-tris-(4-carboxymethylphenyl) porphyrin (P3.2), and 5-(2,4-dihydroxyphenyl)-10,15,20-tris-(4-acetoxy-3-methoxyphenyl) porphyrin (P4.2), along with their fully symmetrical counterparts 5,10,15,20-tetrakis-(4-acetoxy-3-methoxyphenyl) porphyrin (P2.1) and 5,10,15,20-tetrakis-(4-carboxymethylphenyl) porphyrin (P3.1) were comparatively evaluated. The absorption and fluorescence properties, as well as atomic force microscopy measurements were performed to evaluate the photophysical characteristics as well as morphological and textural properties of the mentioned porphyrins. The cellular uptake of compounds and the effect of photodynamic therapy on the viability, proliferation, and necrosis of human HaCaT keratinocytes, human Hs27 skin fibroblasts, human skin SCL II squamous cell carcinoma, and B16F10 melanoma cells were assessed in vitro, in correlation with the structural and photophysical properties of the investigated porphyrins, and with the predictions regarding diffusion through cell membranes and ADMET properties. All samples were found to be isotropic and self-similar, with slightly different degrees of aggregability, had a relatively low predicted toxicity (class V), and a predicted long half-life after systemic administration. The in vitro study performed on non-malignant and malignant skin-relevant cells highlighted that the asymmetric P2.2 porphyrin qualified among the five investigated porphyrins to be a promising photosensitizer candidate for PDT in skin disorders. P2.2 was shown to accumulate well within cells, and induced by PDT a massive decrease in the number of metabolically active skin cells, partly due to cell death by necrosis. P2.2 had in this respect a better behavior than the symmetric P.2.1 compound and the related asymmetric compound P4.2. The strong action of P2.2-mediated PDT on normal skin cells might be an important drawback for further development of this compound. Meanwhile, the P3.1 and P3.2 compounds were not able to accumulate well in skin cells, and did not elicit significant PDT in vitro. Taken together, our experiments suggest that P2.2 can be a promising candidate for the development of novel photosensitizers for PDT in skin disorders.

Discovery of New Microbial Collagenase Inhibitors.

Bacterial virulence factors are mediating bacterial pathogenesis and infectivity. Collagenases are virulence factors secreted by several bacterial stains, such as Clostridium, Bacillus, Vibrio and Pseudomonas. These enzymes are among the most efficient degraders of collagen, playing a crucial role in host colonization. Thus, they are an important target for developing new anti-infective agents because of their pivotal roles in the infection process. A primary screening using a fluorescence resonance energy-transfer assay was used to experimentally evaluate the inhibitory activity of 77 compounds on collagenase A. Based on their inhibitory activity and chemical diversity, a small number of compounds was selected to determine the corresponding half maximal inhibitory con-centration (IC50). Additionally, we used molecular docking to get a better understanding of the enzyme-compound interaction. Several natural compounds (capsaicin, 4',5-dihydroxyflavone, curcumin, dihydrorobinetin, palmatine chloride, biochanin A, 2'-hydroxychalcone, and juglone) were identified as promising candidates for further development into useful anti-infective agents against infections caused by multi-drug-resistant bacterial pathogens which include collagenase A in their enzymatic set.

In Silico Drug Repurposing Framework Predicts Repaglinide, Agomelatine and Protokylol as TRPV1 Modulators with Analgesic Activity.

Pain is one of the most common symptoms experienced by patients. The use of current analgesics is limited by low efficacy and important side effects. Transient receptor potential vanilloid-1 (TRPV1) is a non-selective cation channel, activated by capsaicin, heat, low pH or pro-inflammatory agents. Since TRPV1 is a potential target for the development of novel analgesics due to its distribution and function, we aimed to develop an in silico drug repositioning framework to predict potential TRPV1 ligands among approved drugs as candidates for treating various types of pain. Structures of known TRPV1 agonists and antagonists were retrieved from ChEMBL databases and three datasets were established: agonists, antagonists and inactive molecules (pIC50 or pEC50 < 5 M). Structures of candidates for repurposing were retrieved from the DrugBank database. The curated active/inactive datasets were used to build and validate ligand-based predictive models using Bemis−Murcko structural scaffolds, plain ring systems, flexophore similarities and molecular descriptors. Further, molecular docking studies were performed on both active and inactive conformations of the TRPV1 channel to predict the binding affinities of repurposing candidates. Variables obtained from calculated scaffold-based activity scores, molecular descriptors criteria and molecular docking were used to build a multi-class neural network as an integrated machine learning algorithm to predict TRPV1 antagonists and agonists. The proposed predictive model had a higher accuracy for classifying TRPV1 agonists than antagonists, the ROC AUC values being 0.980 for predicting agonists, 0.972 for antagonists and 0.952 for inactive molecules. After screening the approved drugs with the validated algorithm, repaglinide (antidiabetic) and agomelatine (antidepressant) emerged as potential TRPV1 antagonists, and protokylol (bronchodilator) as an agonist. Further studies are required to confirm the predicted activity on TRPV1 and to assess the candidates' efficacy in alleviating pain.

Identifying FAAH Inhibitors as New Therapeutic Options for the Treatment of Chronic Pain through Drug Repurposing.

Chronic pain determines a substantial burden on individuals, employers, healthcare systems, and society. Most of the affected patients report dissatisfaction with currently available treatments. There are only a few and poor therapeutic options-some therapeutic agents are an outgrowth of drugs targeting acute pain, while others have several serious side effects. One of the primary degradative enzymes for endocannabinoids, fatty acid amide hydrolase (FAAH) attracted attention as a significant molecular target for developing new therapies for neuropsychiatric and neurological diseases, including chronic pain. Using chemical graph mining, quantitative structure-activity relationship (QSAR) modeling, and molecular docking techniques we developed a multi-step screening protocol to identify repurposable drugs as FAAH inhibitors. After screening the DrugBank database using our protocol, 273 structures were selected, with five already approved drugs, montelukast, repaglinide, revefenacin, raloxifene, and buclizine emerging as the most promising repurposable agents for treating chronic pain. Molecular docking studies indicated that the selected compounds interact with the enzyme mostly non-covalently (except for revefenacin) through shape complementarity to the large substrate-binding pocket in the active site. A molecular dynamics simulation was employed for montelukast and revealed stable interactions with the enzyme. The biological activity of the selected compounds should be further confirmed by employing in vitro and in vivo studies.