Novel fluorescence approach for trace quantification of levonorgestrel in breast milk based on click reaction with benzonitrofurazan azide (NBD-AZ).

Although the great importance of oral contraceptive agents in birth control, their existence in breast milk became a cause for concern, since infant exposure to these hormones is associated with many health problems. Consequentially, developing a sensitive bioanalytical method for monitoring their concentrations in breast milk is an urgent demand to examine the safety or the risk of these compounds on infants. Levonorgestrel is one of the most common contraceptive hormones under concern. Despite the high sensitivity of the fluorometric methods, detection of Levonorgestrel by them is confined because its structure does not exhibit any fluorescence. For the first time, we proposed a promising click fluorescent probe, 4-azido-7-nitrobenzoxadiazole to react with the alkyne group of Levonorgestrel, to give a highly fluorescent triazole derivative that exhibited strong signal at wavelength of 544 nm after excitation at 470 nm. Reaction parameters impacting the fluorescence were cautiously studied and optimized. The suggested approach has been successfully applied in Levonorgestrel estimation in breast milk samples with linearity of (0.4-80 ng.ml-1) and low detection limit of 0.12 ng.ml-1without interferences from any biological components and with mean % recovery of 97.84 ± 2.73. Accuracy, sensitivity, selectivity, simplicity, and low-cost makes this approach a convincing, promising, and appealing alternative over reported analytical methods for Levonorgestrel bioanalysis in different matrices.

4-Azido-7-nitrobenzoxadiazole as innovative clickable fluorescence probe for trace and selective quantification of ethinylestradiol in human plasma.

Quantification of ethinylestradiol (EE) in biological matrices is challenging as it is a very potent drug with a very low Cmax (75 pg.ml-1 ). Despite the high sensitivity of fluorometric methods, the detection of EE was confined because its structure exhibited very limited fluorescence. Therefore, it must be derivatized first using a fluorogenic agent to produce a more potent fluorescence derivative to achieve the desired ultrasensitive bioanalysis. Here, for the first time, we proposed a promising click fluorescent probe, 4-azido-7-nitrobenzoxadiazole (NBD-AZ) to react with the alkyne group of EE, with the help of copper sulphate and l-ascorbic acid to give a highly fluorescent and stable 1,2,3-triazole derivative. Density functional theory calculation revealed how the triazole formation affects the quantum yield and fluorescence of click reaction product when compared with NBD-AZ. The resulting triazole exhibited a strong signal at a wavelength of 540 nm after excitation at 470 nm. Reaction parameters impacting the intensity of fluorescence were cautiously studied and optimized. The suggested approach has shown outstanding performance, high linearity (25-300 pg.ml-1 ) and a low detection limit of 7.5 pg.ml-1 . The enhanced sensitivity and selectivity were exploited for analyzing EE in plasma using liquid-liquid extraction for samples cleaning up without interference from any biological components and with a mean % recovery of 100.13 ± 0.39. Accuracy, sensitivity, selectivity, simplicity, and cost-effectiveness make this approach a convincing, promising, and appealing alternative to the reported analytical methods for EE bioanalysis in different matrices.

Betanin improves motor function and alleviates experimental Parkinsonism via downregulation of TLR4/MyD88/NF-κB pathway: Molecular docking and biological investigations.

Parkinson's disease (PD) is a progressive neuroinflammatory and degenerative disease. In this study, we investigated the neuroprotective action of betanin in the rotenone-induced Parkinson-like mice model. Twenty-eight adult male Swiss albino mice were divided into four groups: Vehicle, Rotenone, Rotenone + Betanin 50 mg/kg, and Rotenone + Betanin 100 mg/kg. Parkinsonism was induced by subcutaneous injection of 9 doses of rotenone (1 mg/kg/48 h) plus betanin at 50 and 100 mg/kg/48 h in rotenone + betanin groups for twenty days. Motor dysfunction was assessed after the end of the therapeutic period using the pole, rotarod, open-field, grid, and cylinder tests. Malondialdehyde, reduced glutathione (GSH), Toll-like receptor 4 (TLR4), myeloid differentiation primary response-88 (MyD88), nuclear factor kappa- B (NF-κB), neuronal degeneration in the striatum were evaluated. In addition, we assessed the immunohistochemical densities of tyrosine hydroxylase (TH) in Str and in substantia nigra compacta (SNpc). Our results showed that rotenone remarkably decreased (results of tests), increased decreased TH density with a significant increase in MDA, TLR4, MyD88, NF-κB, and a decrease in GSH (p < 0.05). Treatment with betanin significantly results of tests), increased TH density. Furthermore, betanin significantly downregulated malondialdehyde and improved GSH. Additionally, the expression of TLR4, MyD88, and NF-κB was significantly alleviated. Betanin's powerful antioxidative and anti-inflammatory properties can be related to its neuroprotective potential as well as its ability to delay or prevent neurodegeneration in PD.

Structure-based design of novel melanin-concentrating hormone receptor-1 ligands based on saturated nitrogen-containing heterocycles.

Melanin Concentrating Hormone (MCH) receptor is a G protein-coupled receptor (GPCR) with two subtypes R1 and R2. MCH-R1 is involved in the control of energy homeostasis, feeding behavior and body weight. Many studies have proved that administration of MCH-R1 antagonists significantly reduces food intake and causes weight loss in animal models. Herein, we report the optimization of our previously reported virtual screening hits into novel MCH-R1 ligands with chiral aliphatic nitrogen-containing scaffolds. The activity was improved from the micromolar range of the initial leads to 7 nM. We also disclose the first MCH-R1 ligands based on a diazaspiro[4.5]decane nucleus with sub-micromolar activity. A potent MCH-R1 antagonist with acceptable pharmacokinetic profile could represent a new hope for the management of obesity.

Evaluation of the Effect of Different Construction Techniques of CAD-CAM Milled, 3D-Printed, and Polyamide Denture Base Resins on Flexural Strength: An In Vitro Comparative Study.

PURPOSE: To compare the flexural strength of computer-aided design and computer-aided manufacturing (CAD-CAM) milled denture base resin (DBR), 3D-printed DBR, polyamide, and conventional compression-molded DBR. MATERIALS AND METHODS: Six denture base resins were used, one conventional heat-polymerized (Vertex), two milled CAD-CAM (AvaDent and Polident), two 3D-printed (Harz and NextDent), and one flexible polyamide (Polyamide). According to ISO 20795-1:2013, 60 specimens (65×10×3 mm) were constructed and divided into six groups (n = 10), according to DBR type. The flexural strength was measured using a universal testing machine and three-point loading test. Data were collected and analyzed using one-way ANOVA and Tukey's pair-wise post hoc tests (α = 0.05). RESULTS: One-way ANOVA results showed significant differences in flexural strengths between the tested DBRs (p˂0.001). Milled denture base resins (AvaDent and Polident) had significantly higher flexural strength values than the other groups (p˂0.001) and were followed by Vertex and NextDent, while Polyamide and Harz had the lowest values. Polyamide and Harz denture base resins had significantly lower flexural strength values than conventional denture base resin (p˂0.001). CONCLUSION: CAD-CAM milled DBRs showed the highest flexural strength when compared with conventional compression-molded or 3D-printed DBRs, while 3D-printed DBRs and polyamide showed the lowest flexural strengths.

Structural basis for the selectivity of 3rd generation EGFR inhibitors: a molecular dynamics study.

Activating mutations in the EGFR kinase domain are known to be a common cause of Non-Small Cell Lung Cancer (NSCLC) and are thus targeted for treatment. First generation Tyrosine Kinase Inhibitors (TKIs) were used to treat NSCLC patients with the known activating mutations L858R and exon 19 deletion but were resisted by a second mutation T790M in the active site of the kinase domain. Second generation members of TKIs have an electrophilic moiety that can form a covalent bond with Cys797 and are effective against T790M EGFR but are toxic because they inhibit WT EGFR as well. Third generation TKIs, like Osimertinib, can bind to and irreversibly inhibit T790M mutants selectively, while sparing the wild-type enzyme. Thus, they possess a better safety profile and a wider therapeutic window. However, the reason behind their selectivity is still not well understood. In this study, computational MD simulations were carried out on Osimertinib in complex with both WT and L858R/T790M Double Mutant (DM) EGFR to provide an insight into the selectivity of Osimertinib and its molecular interactions within the active site. A high-resolution trajectory analysis showed that the key selectivity residues are Val726, met793, and Cys797. Interaction of Osimertinib with these residues is improved due to the T790M mutation which optimizes the ligand orientation for binding, as evident from the RMSD and the distances monitored. These results can provide guidance for the development of more selective 3rd generation EGFR TKIs.Communicated by Ramaswamy H. Sarma.

Microfluidic-Based Formulation of Essential Oils-Loaded Chitosan Coated PLGA Particles Enhances Their Bioavailability and Nematocidal Activity.

In this study, poly (lactic-co-glycolic) acid (PLGA) particles were synthesized and coated with chitosan. Three essential oil (EO) components (eugenol, linalool, and geraniol) were entrapped inside these PLGA particles by using the continuous flow-focusing microfluidic method and a partially water-miscible solvent mixture (dichloromethane: acetone mixture (1:10)). Encapsulation of EO components in PLGA particles was confirmed by Fourier transform infrared spectroscopy, thermogravimetric analysis, and X-ray diffraction, with encapsulation efficiencies 95.14%, 79.68%, and 71.34% and loading capacities 8.88%, 8.38%, and 5.65% in particles entrapped with eugenol, linalool, and geraniol, respectively. The EO components' dissociation from the loaded particles exhibited an initial burst release in the first 8 h followed by a sustained release phase at significantly slower rates from the coated particles, extending beyond 5 days. The EO components encapsulated in chitosan coated particles up to 5 µg/mL were not cytotoxic to bovine gut cell line (FFKD-1-R) and had no adverse effect on cell growth and membrane integrity compared with free EO components or uncoated particles. Chitosan coated PLGA particles loaded with combined EO components (10 µg/mL) significantly inhibited the motility of the larval stage of Haemonchus contortus and Trichostrongylus axei by 76.9%, and completely inhibited the motility of adult worms (p < 0.05). This nematocidal effect was accompanied by considerable cuticular damage in the treated worms, reflecting a synergistic effect of the combined EO components and an additive effect of chitosan. These results show that encapsulation of EO components, with a potent anthelmintic activity, in chitosan coated PLGA particles improve the bioavailability and efficacy of EO components against ovine gastrointestinal nematodes.

Identification of Novel 2,4,5-Trisubstituted Pyrimidines as Potent Dual Inhibitors of Plasmodial PfGSK3/PfPK6 with Activity against Blood Stage Parasites In Vitro.

Essential plasmodial kinases PfGSK3 and PfPK6 are considered novel drug targets to combat rising resistance to traditional antimalarial therapy. Herein, we report the discovery of IKK16 as a dual PfGSK3/PfPK6 inhibitor active against blood stage Pf3D7 parasites. To establish structure-activity relationships for PfPK6 and PfGSK3, 52 analogues were synthesized and assessed for the inhibition of PfGSK3 and PfPK6, with potent inhibitors further assessed for activity against blood and liver stage parasites. This culminated in the discovery of dual PfGSK3/PfPK6 inhibitors 23d (PfGSK3/PfPK6 IC50 = 172/11 nM) and 23e (PfGSK3/PfPK6 IC50 = 97/8 nM) with antiplasmodial activity (23d Pf3D7 EC50 = 552 ± 37 nM and 23e Pf3D7 EC50 = 1400 ± 13 nM). However, both compounds exhibited significant promiscuity when tested in a panel of human kinase targets. Our results demonstrate that dual PfPK6/PfGSK3 inhibitors with antiplasmodial activity can be identified and can set the stage for further optimization efforts.

3D-Printed Microfluidics Potential in Combating Future and Current Pandemics (COVID-19).

Coronavirus disease (COVID-19) emerged in China in December 2019. In March 2020, the WHO declared it a pandemic leading to worldwide lockdowns and travel restrictions. By May, it infected 4,789,205 and killed 318,789 people. This led to severe shortages in the medical sector besides devastating socio-economic effects. Many technologies such as artificial intelligence (AI), virtual reality (VR), microfluidics, 3D printing, and 3D scanning can step into contain the virus and hinder its extensive spread. This article aims to explore the potentials of 3D printing and microfluidic in accelerating the diagnosis and monitoring of the disease and fulfilling the shortages of personal protective equipment (PPE) and medical equipment. It highlights the main applications of 3D printers and microfluidics in providing PPE (masks, respirators, face shields, goggles, and isolation chambers/hoods), supportive care (respiratory equipment) and diagnostic supplies (sampling swabs & lab-on-chip) to ease the COVID-19 pressures. Also, the cost of such technology and regulation considerations are addressed. We conclude that 3D printing provided reusable and low-cost solutions to mitigate the shortages. However, safety, sterility, and compatibility with environmental protection standards need to be guaranteed through standardization and assessment by regulatory bodies. Finally, lessons learned from this pandemic can also help the world prepare for upcoming outbreaks.

Discovery of 3-(2-aminoethyl)-thiazolidine-2,4-diones as a novel chemotype of sigma-1 receptor ligands.

Sigma receptor is a transmembrane non-GPCR protein expressed mainly in the endoplasmic reticulum membrane associated with mitochondria. It is classified into two types: Sigma-1 (S1R) and Sigma-2 (S2R) based on their biological functions. S1R has been implicated in many neurological disorders such as anxiety, schizophrenia, and depression. Therefore, S1R ligands possess a variety of potential clinical applications with a great interest in the treatment of neuropathic pain. In this study, we report the discovery of a novel lead compound for S1R binding, based on the thiazolidine-2,4-dione nucleus. We have explored hydrophobic groups of different sizes on both sides of the five-membered ring scaffold guided by the crystal structure of S1R. Six compounds showed more than 50% displacement of the radioligand at 10 µM concentration with compound 6c resulting in 100% displacement and a Ki of 95.5 nM. Moreover, compounds 6c and 6e showed a significant selectivity over S2R. In addition, molecular docking predicted that all the compounds showed the critical salt bridge with Glu172 with variable degrees of π-stacking interaction with Tyr103. Upon optimization, this series of compounds could represent potential clinically useful S1R ligands for pain management.

In-vitro Comparative Evaluation for the Surface Properties and Impact Strength of CAD/CAM Milled, 3D Printed, and Polyamide Denture Base Resins.

Objective: There is a paucity of data regarding the effect of fabrication techniques and compositions of CAD/CAM milled, 3D-printed, and polyamide flexible denture base resin materials (DBRMs) on the surface roughness (SR), surface hardness (SH), and impact strength (IS). Therefore, this study aimed to evaluate the SR, SH, and IS of CAD/CAM milled, 3D-printed, and polyamide flexible DBRMs. Materials and Methods: Ninety specimens were constructed from different DBRMs and divided into three groups (CAD/CAM, 3D-printed, and polyamide DBRMs; n = 30) with specific measurements: 15 × 10 × 2.5 mm for SR and H tests and 80 × 10 × 4 mm notched specimen for IS test. SR meter and Vickers micro SH tester were used to measure SR and SH, respectively, whereas the IS was evaluated using Charpy's impact testing machine. Data were collected and statistically analyzed using one-way analysis of variance and post hoc Tukey's tests (α=0.05). Results: There were significant differences between the tested materials (P< 0.05). The CAD/CAM milled showed lowest SR when compared with 3D-printed resin and polyamide flexible resin (P< 0.05); however, there was a significant increase in SH of CAD/CAM milled and 3D-printed DBRMs when compared with polyamide materials (P< 0.05). There was a significant increase in IS of polyamide and CAD/CAM milled resins when compared with 3D-printed DBRMs (P < 0.05). Conclusion: CAD/CAM milled resins showed high IS and SH with lower SR.

Anticancer Effects of New Ceramides Isolated from the Red Sea Red Algae Hypnea musciformis in a Model of Ehrlich Ascites Carcinoma: LC-HRMS Analysis Profile and Molecular Modeling.

Different classes of phytochemicals were previously isolated from the Red Sea algae Hypnea musciformis as sterols, ketosteroids, fatty acids, and terpenoids. Herein, we report the isolation of three fatty acids-docosanoic acid 4, hexadecenoic acid 5, and alpha hydroxy octadecanoic acid 6-as well as three ceramides-A (1), B (2), and C (3)-with 9-methyl-sphinga-4,8-dienes and phytosphingosine bases. Additionally, different phytochemicals were determined using the liquid chromatography coupled with electrospray ionization high-resolution mass spectrometry (LC-ESI-HRMS) technique. Ceramides A (1) and B (2) exhibited promising in vitro cytotoxic activity against the human breast adenocarcinoma (MCF-7) cell line when compared with doxorubicin as a positive control. Further in vivo study and biochemical estimation in a mouse model of Ehrlich ascites carcinoma (EAC) revealed that both ceramides A (1) and B (2) at doses of 1 and 2 mg/kg, respectively, significantly decreased the tumor size in mice inoculated with EAC cells. The higher dose (2 mg/kg) of ceramide B (2) particularly expressed the most pronounced decrease in serum levels of vascular endothelial growth factor -B (VEGF-B) and tumor necrosis factor-α (TNF-α) markers, as well as the expression levels of the growth factor midkine in tumor tissue relative to the EAC control group. The highest expression of apoptotic factors, p53, Bax, and caspase 3 was observed in the same group that received 2 mg/kg of ceramide B (2). Molecular docking simulations suggested that ceramides A (1) and B (2) could bind in the deep grove between the H2 helix and the Ser240-P250 loop of p53, preventing its interaction with MDM2 and leading to its accumulation. In conclusion, this study reports the cytotoxic, apoptotic, and antiangiogenic effects of ceramides isolated from the Red Sea algae Hypnea musciformis in an experimental model of EAC.

Comparative Effect of Different Surface Treatments on the Shear Bond Strength of Two Types of Artificial Teeth Bonded To Two Types of Denture Base Resins.

PURPOSE: This in vitro study aims to assess the impact of various surface treatments on the shear bond strength (SBS) of two types of artificial teeth and denture base resins (DBRs). MATERIALS AND METHODS: Two types of DBRs (CAD/CAM-milled and heat-polymerized) and two types of denture teeth (acrylic and composite) were investigated. Teeth were cut into slices (5 × 5 × 2 mm) and divided according to surface treatment into four subgroups (n = 10): no treatment (control), air abrasion (Alumina-blasting; AB), bur roughening, and dichloromethane (DCM) subgroups. According to manufacturer recommendations, the treated tooth slices were bonded to the acrylic disk of DBRs. The SBS test was performed using a universal testing machine. ANOVA was used for results analysis followed by Tukey's post hoc tests (α = 0.05). RESULTS: DCM and AB increased the SBS of acrylic teeth to heat-polymerized DBR compared with other groups (p < 0.001). All surface treatments showed no significant difference in CAD/CAM DBR with acrylic teeth (p = 0.059; AB, p = 0.319; bur roughening, p = 0.895; DCM), while there was a significant decrease in SBS with composite teeth (p ˂ 0.001). Between teeth, acrylic teeth showed a statistically significant increase in SBS compared to composite teeth (p < 0.001). CONCLUSION: AB and DCM application improved the SBS for acrylic teeth with the heat-polymerized DBR when compared with the untreated group, but none of the surface treatment agents showed significant improvement with CAD/CAM DBR. All surface treatment agents reduced the SBS for composite teeth with CAD/CAM DBR while AB only increased the SBS with heat-polymerized DBR.

Molecular basis of the potential interaction of SARS-CoV-2 spike protein to CD147 in COVID-19 associated-lymphopenia.

Lymphopenia is considered one of the most characteristic clinical features of the coronavirus disease 2019 (COVID-19). SARS-CoV-2 infects host cells via the interaction of its spike protein with the human angiotensin-converting enzyme 2 (hACE2) receptor. Since T lymphocytes display a very low expression level of hACE2, a novel receptor might be involved in the entry of SARS-CoV-2 into T cells. The transmembrane glycoprotein CD147 is highly expressed by activated T lymphocytes, and was recently proposed as a probable route for SARS-CoV-2 invasion. To understand the molecular basis of the potential interaction of SARS-CoV-2 to CD147, we have investigated the binding of the viral spike protein to this receptor in-silico. The results showed that this binding is dominated by electrostatic interactions involving residues Arg403, Asn481, and the backbone of Gly502. The overall binding arrangement shows the CD147 C-terminal domain interacting with the spike external subdomain in the grove between the short antiparallel ß strands, ß1' and ß2', and the small helix α1'. This proposed interaction was further confirmed using MD simulation and binding free energy calculation. These data contribute to a better understanding of the mechanism of infection of SARS-CoV-2 to T lymphocytes and could provide valuable insights for the rational design of adjuvant treatment for COVID-19. Communicated by Ramaswamy H. Sarma.

Strength and Surface Properties of a 3D-Printed Denture Base Polymer.

PURPOSE: This in vitro study evaluated the flexural strength, impact strength, hardness, and surface roughness of 3D-printed denture base resin subjected to thermal cycling treatment. MATERIALS AND METHODS: According to ISO 20795-1:2013 standards, 120 acrylic resin specimens (40/flexural strength test, 40/impact strength, and 40/surface roughness and hardness test, n = 10) were fabricated and distributed into two groups: heat-polymerized; (Major.Base.20) as control and 3D-printed (NextDent) as experimental group. Half of the specimens of each group were subjected to 10,000 thermal cycles of 5 to 55°C simulating 1 year of clinical use. Flexural strength (MPa), impact strength (KJ/m2 ), hardness (VHN), and surface roughness (µm) were measured using universal testing machine, Charpy's impact tester, Vickers hardness tester, and profilometer, respectively. Data were analyzed by ANOVA and Tukey honestly significant difference (HSD) test (α = 0.05). RESULTS: The values of flexural strength (MPa) were 86.63 ± 1.0 and 69.15 ± 0.88; impact strength (KJ/m2 )-6.32 ± 0.50 and 2.44 ± 0.31; hardness (VHN)-41.63 ± 2.03 and 34.62 ± 2.1; and surface roughness (µm)-0.18 ± 0.01 and 0.12 ± 0.02 for heat-polymerized and 3D-printed denture base materials, respectively. Significant differences in all tested properties were recorded between heat-polymerized and 3D-printed denture base materials (P < 0.001). Thermal cycling significantly lowered the flexural strength (63.93 ± 1.54 MPa), impact strength (2.40 ± 0.35 KJ/m2 ), and hardness (30.17 ± 1.38 VHN) of 3D-printed resin in comparison to thermal cycled heat-polymerized resin, but surface roughness showed non-significant difference (p = 0.262). CONCLUSION: 3D-printed resin had inferior flexural strength, impact strength, and hardness values than heat-polymerized resin, but showed superior surface roughness. Temperature changes (thermal cycling) significantly reduced the hardness and flexural strength and increased surface roughness, but did not affect the impact strength.

Nifuroxazide Mitigates Angiogenesis in Ehlrich's Solid Carcinoma: Molecular Docking, Bioinformatic and Experimental Studies on Inhibition of Il-6/Jak2/Stat3 Signaling.

Nifuroxazide is an antidiarrheal medication that has promising anticancer activity against diverse types of tumors. The present study tested the anticancer activity of nifuroxazide against Ehrlich's mammary carcinoma grown in vivo. Furthermore, we investigated the effect of nifuroxazide on IL-6/jak2/STAT3 signaling and the possible impact on tumor angiogenesis. The biological study was supported by molecular docking and bioinformatic predictions for the possible effect of nifuroxazide on this signaling pathway. Female albino mice were injected with Ehrlich carcinoma cells to produce Ehrlich's solid tumors (ESTs). The experimental groups were as follows: EST control, EST + nifuroxazide (5 mg/kg), and EST + nifuroxazide (10 mg/kg). Nifuroxazide was found to reduce tumor masses (730.83 ± 73.19 and 381.42 ± 109.69 mg vs. 1099.5 ± 310.83) and lessen tumor pathologies. Furthermore, nifuroxazide downregulated IL-6, TNF-α, NFk-ß, angiostatin, and Jak2 proteins, and it also reduced tumoral VEGF, as indicated by ELISA and immunohistochemical analysis. Furthermore, nifuroxazide dose-dependently downregulated STAT3 phosphorylation (60% and 30% reductions, respectively). Collectively, the current experiment shed light on the antitumor activity of nifuroxazide against mammary solid carcinoma grown in vivo. The antitumor activity was at least partly mediated by inhibition of IL-6/Jak2/STAT3 signaling that affected angiogenesis (low VEGF and high angiostatin) in the EST. Therefore, nifuroxazide might be a promising antitumor medication if appropriate human studies will be conducted.

Metal dichalcogenide nanomeshes: structural, electronic and magnetic properties.

Motivated by the successful preparation of two-dimensional transition metal dichalcogenide (2D-TMD) nanomeshes in the last three years, we use density functional theory (DFT) to study the structural stability, mechanical, magnetic, and electronic properties of porous 2H-MoX2 (X = S, Se and Te) without and with pore passivation. We consider structures with multiple, systematically created pores. The molecular dynamics simulations and cohesive energy calculations showed the stability of the 2D-TMD nanomeshes, with larger stability for those with smaller pores. The lattice undergoes some deformations to accommodate the pore energetically, and as the pore size increases Young's modulus decreases. In most cases, the missing metal atoms disrupt the spin states' even population, resulting in some nanomeshes becoming magnetic. The electronic gaps of the MoX2 nanomesh systems are diminished because of the emergence of pore-edge localized mid-gap metal 4d states in the spin-polarized spectrum, making some systems half-metallic. The oxygen passivation of the pore edges of 2D-TMD nanomeshes restores the even population of spin states, and makes those systems metallic. Our results can be used in different applications such as spintronics, ion chelation, and molecular sensing applications.

Recent Advances in the Development of Sigma Receptor Ligands as Cytotoxic Agents: A Medicinal Chemistry Perspective.

Since their discovery as distinct receptor proteins, the specific physiopathological role of sigma receptors (σRs) has been deeply investigated. It has been reported that these proteins, classified into two subtypes indicated as σ1 and σ2, might play a pivotal role in cancer growth, cell proliferation, and tumor aggressiveness. As a result, the development of selective σR ligands with potential antitumor properties attracted significant attention as an emerging theme in cancer research. This perspective deals with the recent advances of σR ligands as novel cytotoxic agents, covering articles published between 2010 and 2020. An up-to-date description of the medicinal chemistry of selective σ1R and σ2R ligands with antiproliferative and cytotoxic activities has been provided, including major pharmacophore models and comprehensive structure-activity relationships for each main class of σR ligands.

Deciphering the molecular basis of the kappa opioid receptor selectivity: A Molecular Dynamics study.

Selective antagonists for the kappa opioid receptor (KOP) have the potential to treat opiate and alcohol addiction, as well as depression and other CNS disorders. Over the years, the development of KOP-selective antagonists yielded very few successful compounds. Recently, N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines have emerged as a novel class of pure opioid receptor antagonists, including the marketed Mu opioid receptor (MOP) peripheral antagonist Alvimopan and the potent KOP antagonist JDTic. However, the selectivity determinants of this class of compounds towards the opioid receptor subtypes are still vague and understudied. In this work, we have performed Molecular Dynamics (MD) simulation to gain insights into the differential binding of this class of compounds into KOP, as exemplified by Alvimopan and JDTic. Our study indicated that the selectivity largely depends on ligands interaction with the selectivity pocket formed by Val108, Thr111, and Val118, supported by two additional polar and hydrophobic contacts with Asp138 and Trp287, respectively. Our results also demonstrate, for the first time, that non-morphinan ligands can still adopt the "message-address model" for KOP efficacy and selectivity by binding to Glu297.

Interaction of nanoparticles with biological macromolecules: a review of molecular docking studies.

The high frequency of using engineered nanoparticles in various medical applications entails a deep understanding of their interaction with biological macromolecules. Molecular docking simulation is now widely used to study the binding of different types of nanoparticles with proteins and nucleic acids. This helps not only in understanding the mechanism of their biological action but also in predicting any potential toxicity. In this review, the computational techniques used in studying the nanoparticles interaction with biological macromolecules are covered. Then, a comprehensive overview of the docking studies performed on various types of nanoparticles will be offered. The implication of these predicted interactions in the biological activity and/or toxicity is also discussed for each type of nanoparticles.