Molecular docking,pharmacophore based virtual screening and molecular dynamics studies towards the identification of potential leads for the management of H. pylori

The enzyme pantothenate synthetase panC is one of the potential new antimicrobial drug targets, but it is poorly characterized in H. pylori. H. pylori infection can cause gastric cancer and the management of H. pylori infection is crucial in various gastric ulcers and gastric cancer. The current study describes the use of innovative drug discovery and design approaches like comparative metabolic pathway analysis (Metacyc), exploration of database of essential genes (DEG), homology modelling, pharmacophore based virtual screening, ADMET studies and molecular dynamics simulations in identifying potential lead compounds for the H. pylori specific panC. The top ranked virtual hits STOCK1N-60270, STOCK1N-63040, STOCK1N-44424 and STOCK1N-63231 can act as templates for synthesis of new H. pylori inhibitors and they hold a promise in the management of gastric cancers caused by H. pylori.

Computational approaches such as pharmacophore modeling, virtual screening and MD simulations were explored to find the potential hits as H. pylori specific panC inhibitors for the management of gastric ulcers and gastric cancers.     

Mediation of a non-proteolytic activation of complement component C3 by phospholipid vesicles

Liposomes are becoming increasingly important as drug delivery systems, to target a drug to specific cells and tissues and thereby protecting the recipient from toxic effects of the contained drug. Liposome preparations have been described to activate complement. In this study, we have investigated complement activation triggered by neutral dimyristoyl-phosphocholine (DMPC) liposomes in human plasma and whole-blood systems. Incubation in plasma led to the generation of complement activation products (C3a and sC5b-9). Unexpectedly, investigations of surface-bound C3 revealed contact activated, conformationally changed C3 molecules on the liposomes. These changes were characterized by Western blotting with C3 monoclonal antibodies, and by incubating liposomes with purified native C3 and factors I and H. Quartz crystal microbalance analysis confirmed binding of C3 to planar DMPC surfaces. In addition, we demonstrated that DMPC liposomes bound to or were phagocytized by granulocytes in a complement-dependent manner, as evidenced by the use of complement inhibitors. In summary, we have shown that C3 is activated both by convertase-dependent cleavage, preferentially in the fluid phase, by mechanisms which are not well elucidated, and also by contact activation into C3(H₂O) on the DMPC surface. In particular, this contact activation has implications for the therapeutic regulation of complement activation during liposome treatment.     

Utero-cutaneous fistula following cesarean section: A case report

Utero-cutaneous fistula is a rare pathology. It mostly occurs consecutively to surgical intervention such as Cesarean section. Blood discharge from the cesarean scar during menstruation is a quasi-pathognomonic feature. Imaging modalities, particularly with the injection of contrast material through the cutaneous fistulous opening, confirm the diagnosis. The management is mainly surgical.We report the case of a utero-cutaneous fistula in a 27-year-old lady, with systemic lupus erythematosus. She presented seven months after her third cesarean section with pain and blood discharge from the cutaneous scar during menstruation for four months. A pelvic CT scan with the injection of the contrast material through the cutaneous fistulous opening confirmed the diagnosis of utero-cutaneous fistula. Surgical management was successful.     

In silico identification of potential SARS COV-2 2′-O-methyltransferase inhibitor: fragment-based screening approach and MM-PBSA calculations

In the present era, there are many efforts trying to face the emerging and successive waves of the COVID-19 pandemic. This has led to considering new and unusual targets for SARS CoV-2. 2′-O-Methyltransferase (nsp16) is a key and attractive target in the SARS CoV-2 life cycle since it is responsible for the viral RNA protection via a cap formation process. In this study, we propose a new potential inhibitor for SARS COV-2 2′-O-methyltransferase (nsp16). A fragment library was screened against the co-crystal structure of the SARS COV-2 2′-O-methyltransferase complexed with Sinefungin (nsp16 – PDB ID: 6WKQ), and consequently the best proposed fragments were linked via a de novo approach to build molecule AP-20. Molecule AP-20 displayed a superior docking score to Sinefungin and reproduced the key interactions in the binding site of 2′-O-methyltransferase. Three molecular dynamic simulations of the 2′-O-methyltransferase apo structure and its complexed forms with AP-20 and Sinefungin were performed for 150 nano-seconds to provide insights on the dynamic nature of such setups and to assess the stability of the proposed AP-20/enzyme complex. AP-20/enzyme complex demonstrated better stability for the ligand–enzyme complex compared to Sinefungin in a respective setup. Furthermore, MM-PBSA binding free energy calculations showed a better profile for AP-20/enzyme complex compared to Sinefungin/enzyme complex emphasizing the potential inhibitory effect of AP-20 on SARS COV-2 2′-O-methyltransferase. We endorse our designed molecule AP-20 to be further explored via experimental evaluations to confront the spread of the emerging COVID-19. Also, in silico ADME profiling has ascribed to AP-20 an excellent safety and metabolic stability profile.

The identification of AP-20 as a potential SARS COV-2 2′-O-methyltransferase inhibitor: fragment-based screening approach and MM-PBSA calculations.     

A simple single jar “on–off fluorescence” designed system for the determination of mitoxantrone using an eosin Y dye in raw powder,vial, and human biofluids

In this work, a direct, simple, one-pot, and green spectrofluorimetric approach was applied to measure mitoxantrone, a chemotherapeutic agent, through a green validated method. The suggested approach focused on establishing an easy association complex combining mitoxantrone and the eosin Y reagent in a slightly acidic solution. The fluorometric analysis was dependent on off-mitoxantrone action on the emission intensity of the dye (eosin Y) at 544.5 nm (excitation = 301 nm). The devised system has a linear range of 0.07–2.5 μg mL⁻¹ and a detection limit of 0.016 μg mL⁻¹. All system parameters for the formation of mitoxantrone–eosin Y complexes were modulated analytically. Also, the system was reviewed in agreement with ICH criteria. Furthermore, the proposed model was approached to quantify mitoxantrone in its pharmaceutical vial dosage form with high recoveries. Also, the proposed spectroscopic design was efficiently employed to detect the investigated drug in body fluids (blood and urine). Lastly, the designed method was evaluated from a greenness point of view according to eco-scale.

This work describes a green fluorescence on–off system that relies on establishing a simple ion association complex pairing the mitoxantrone antineoplastic drug with the eosin Y reagent in a slightly acidic solution.     

Management of maxillary impacted canines: A prospective study of orthodontists' preferences

BackgroundMaxillary canines are considered the most commonly impacted teeth, after the third molars. Orthodontists have different preferences on how to approach maxillary impacted canines (MIC). The objective of this article was to investigate orthodontists’ approach to managing MIC.Material and methodsA cross-sectional study comprising a comprehensive survey with 22 questions was sent to practicing orthodontists. This study explored the preferred diagnostic measures, surgical techniques, materials, and mechanics utilized to manage MIC;104 responses were returned.ResultsPalatal impaction was reported to be encountered more often than labial impaction by 60% of the respondents. In 62% of the respondents, an oral and maxillofacial surgeon was the specialist preferred to perform the surgical exposure. In 66%, the choice of required surgical techniques was reported as a joint decision between orthodontists and other specialists who perform the surgery. Cone-beam computed tomography (CBCT) was reported to be the diagnostic x-ray of choice. The gold button with a chain was the preferred bonded attachment in 86% of cases. Less than half of the respondents bonded the attachments themselves during surgical exposure. A clear plastic retainer was the preferred retainer in 61% of the respondents, and 43% of the respondents tended to use a closed exposure technique. Coe-pak^TM was the preferred surgical pack for orthodontists who prefer an open exposure technique. Piggyback (double wire) was the preferable mechanic to move a palatally impacted canine.ConclusionOur findings indicate that there are variations among orthodontists on how to manage MICs in terms of diagnostic methods, surgical management, materials, and mechanics.