Therapeutic Path to Triple Knockout: Investigating the Pan-inhibitory Mechanisms of AKT, CDK9, and TNKS2 by a novel 2-Phenylquinazolinone derivative in Cancer Therapy- An In-Silico Investigation.

BACKGROUND: Blocking the oncogenic Wnt//ß-catenin pathway has of late been investigated as a viable therapeutic approach in the treatment of cancer. This involves the multi-targeting of certain members of the tankyrase-kinase family; tankyrase 2 (TNKS2), protein kinase B (AKT), and cyclin-dependent kinase 9 (CDK9), which propagate the oncogenic Wnt/ß-catenin signalling pathway. METHODS: During a recent investigation, the pharmacological activity of 2-(4-aminophenyl)-7-chloro-3H-quinazolin-4-one was repurposed to serve as a 'triple-target' inhibitor of TNKS2, AKT and CDK9. Yet, the molecular mechanism that surrounds its multi-targeting activity remains unanswered. As such, this study aims to explore the pan-inhibitory mechanism of 2-(4-aminophenyl)-7-chloro-3H-quinazolin-4-one towards AKT, CDK9, and TNKS2, using in silico techniques. RESULTS: Results revealed favourable binding affinities of -34.17 kcal/mol, -28.74 kcal/mol, and -27.30 kcal/mol for 2-(4-aminophenyl)-7-chloro-3H-quinazolin-4-one towards TNKS2, CDK9, and AKT, respectively. Pan-inhibitory binding of 2-(4-aminophenyl)-7-chloro-3H-quinazolin-4-one is illustrated by close interaction with specific residues on tankyrase-kinase. Structurally, 2-(4-aminophenyl)-7-chloro-3H-quinazolin-4-one had an impact on the flexibility, solvent-accessible surface area, and stability of all three proteins, which was illustrated by numerous modifications observed in the unbound as well as the bound states of the structures, which evidenced the disruption of their biological function. Prediction of the pharmacokinetics and physicochemical properties of 2-(4-aminophenyl)-7-chloro-3H-quinazolin-4-one further established its inhibitory potential, evidenced by the favourable absorption, metabolism, excretion, and minimal toxicity properties. CONCLUSION: The following structural insights provide a starting point for understanding the pan-inhibitory activity of 2-(4-aminophenyl)-7-chloro-3H-quinazolin-4-one. Determining the criticality of the interactions that exist between the pyrimidine ring and catalytic residues could offer insight into the structure-based design of innovative tankyrase-kinase inhibitors with enhanced therapeutic effects.

In-Silico Mining of the Toxins Database (T3DB) towards Hunting Prospective Candidates as ABCB1 Inhibitors: Integrated Molecular Docking and Lipid Bilayer-Enhanced Molecular Dynamics Study.

Multidrug resistance (MDR) is one of the most problematic issues in chemotherapeutic carcinoma therapy. The ABCB1 transporter, a drug efflux pump overexpressed in cancer cells, has been thoroughly investigated for its association with MDR. Thus, discovering ABCB1 inhibitors can reverse the MDR in cancer cells. In the current work, a molecular docking technique was utilized for hunting the most prospective ABCB1 inhibitors from the Toxin and Toxin-Target Database (T3DB). Based on the docking computations, the most promising T3DB compounds complexed with the ABCB1 transporter were subjected to molecular dynamics (MD) simulations over 100 ns. Utilizing the MM-GBSA approach, the corresponding binding affinities were computed. Compared to ZQU (calc. -49.8 kcal/mol), Emamectin B1a (T3D1043), Emamectin B1b (T3D1044), Vincristine (T3D4016), Vinblastine (T3D4017), and Vindesine (T3D2479) complexed with ABCB1 transporter demonstrated outstanding binding affinities with ΔGbinding values of -93.0, -92.6, -93.8, -92.2, and -90.8 kcal/mol, respectively. The structural and energetic investigations confirmed the constancy of the identified T3DB compounds complexed with the ABCB1 transporter during the 100 ns MD course. To mimic the physiological conditions, MD simulations were conducted for those identified inhibitors complexed with ABCB1 transporter in the presence of a POPC membrane. These findings revealed that Emamectin B1a, Emamectin B1b, Vincristine, Vinblastine, and Vindesine are promising ABCB1 inhibitors that can reverse the MDR. Therefore, subjecting those compounds to further in-vitro and in-vivo investigations is worthwhile.

Development of ZnO-GO-NiO membrane for removal of lead and cadmium heavy metal ions from wastewater.

The presence of heavy metal (HM) ions, such as lead, cadmium, and chromium in industrial wastewater discharge are major contaminants that pose a risk to human health. These HMs should separate from the wastewater to ensure the reuse of the discharged water in the process and mitigate their environmental impacts. The distinctive mechanical properties of 2D graphene oxide (GO), and the antifouling characteristics of metal oxides (ZnO/NiO) nanoparticles combined to produce composites supporting special features for wastewater treatment. This study employed solution casting and phase inversion methods to synthesize PSF-based GO, ZnO-GO, and ZnO-GO-NiO mixed matrix membranes and the effects of variation in composition on the removal of lead (Pb2+) and cadmium (Cd2+) ion was examined. Several characterization techniques including X-ray diffraction analysis, scanning electron microscopy, energy dispersive X-ray, and Fourier transform infrared spectroscopy were applied to analyze the synthesized NPs and MMMs. The composite membranes were also analyzed in terms of their porosity, permeability, hydrophilicity, surface roughness, zeta potential, thermal stability, mechanical strength, and flux regeneration at various transmembrane pressures (2-3 kgcm-2), and pH value (5.5). The highest adsorption capacities were measured to be 308.16 mg g-1 and 354.80 mg g-1 for Pb (II) and Cd (II), respectively, for membrane (M4_A) having 0.3 wt% of ZnO-GO-NiO nanocomposite, at 200 mg L-1 of feed concentration and 1.60 mL min-1 of permeate flux. The Pb (II) and Cd (II) adsorption breakthrough curves were created, and the results of the experiment were compared with the data of the Thomas model.

Multi-dimensional structural footprint identification for the design of potential scaffolds targeting METTL3 in cancer treatment from natural compounds.

CONTEXT: [Formula: see text]-adenosine-methyltransferase (METTL3) is the catalytic domain of the 'writer' proteins which is involved in the post modifications of [Formula: see text]-methyladinosine ([Formula: see text]). Though its activities are essential in many biological processes, it has been implicated in several types of cancer. Thus, drug developers and researchers are relentlessly in search of small molecule inhibitors that can ameliorate the oncogenic activities of METTL3. Currently, STM2457 is a potent, highly selective inhibitor of METTL3 but is yet to be approved. METHODS: In this study, we employed structure-based virtual screening through consensus docking by using AutoDock Vina in PyRx interface and Glide virtual screening workflow of Schrodinger Glide. Thermodynamics via MM-PBSA calculations was further used to rank the compounds based on their total free binding energies. All atom molecular dynamics simulations were performed using AMBER 18 package. FF14SB force fields and Antechamber were used to parameterize the protein and compounds respectively. Post analysis of generated trajectories was analyzed with CPPTRAJ and PTRAJ modules incorporated in the AMBER package while Discovery studio and UCSF Chimera were used for visualization, and origin data tool used to plot all graphs. RESULTS: Three compounds with total free binding energies higher than STM2457 were selected for extended molecular dynamics simulations. The compounds, SANCDB0370, SANCDB0867, and SANCDB1033, exhibited stability and deeper penetration into the hydrophobic core of the protein. They engaged in relatively stronger intermolecular interactions involving hydrogen bonds with resultant increase in stability, reduced flexibility, and decrease in the surface area of the protein available for solvent interactions suggesting an induced folding of the catalytic domain. Furthermore, in silico pharmacokinetics and physicochemical analysis of the compounds revealed good properties suggesting these compounds could serve as promising MEETL3 entry inhibitors upon modifications and optimizations as presented by natural compounds. Further biochemical testing and experimentations would aid in the discovery of effective inhibitors against the berserk activities of METTL3.

One-Step Synthesis of New Amphiphilic Nonionic Surfactants Based on Alkylamine and Poly(ethylene glycol) Dimethacrylate for Demulsification of Arabian Heavy Crude Oil Emulsions.

New non-ionic surfactants based on alkylamine and poly(ethylene glycol) dimethacrylate were synthesized by one-step Aza-Michael addition reaction. The surfactants' chemical compositions, surface and interfacial activities, micellization, and zeta potential were characterized. Their surface and interfacial activities recommended the application as demulsifiers for water in Arabian heavy oil emulsions (w/o). The demulsification of this type of emulsion has attracted researchers' attention because of its high stability with water droplets in the microscale. The outcome of using the prepared surfactants showed high performance as emulsion breakers, as the demulsification efficiency reached 100% for w/o emulsions with different water to oil ratios (50:50, 30:70, and 10:90).

Clinical and Urodynamic Findings Before and After Surgical Repair of Pelvic Organ Prolapse in Women With Lower Urinary Tract Symptoms. A Prospective Observational Study.

OBJECTIVE: To investigate the association between urodynamic findings and lower urinary tract symptoms (LUTS) before and after surgical treatment of pelvic organ prolapse (POP). PATIENTS AND METHODS: Seventy-four patients with stage II or more anterior POP associated with LUTS and eligible for surgical repair of POP were included in this prospective study. All cases had clinical evaluation and urodynamic testing (UDS) before and 6 months after surgical repair of POP. RESULTS: Mean age was 45 ± 9 years. Mean BMI was 28 ± 6 kg/m2. Most cases were multiparous, had stage III cystocele (50/74, 68%), and an associating apical prolapse (37/74, 50%). Native tissue repair was done in 53/74 (72%) cases with a concomitant anti-incontinence procedure in 41/74 (55%) for overt (26/74, 35%) or occult (15/74, 20%) stress urinary incontinence (SUI). Preoperative UDS revealed detrusor overactivity (DO) in 19/56 (34%) patients of those presenting with storage LUTS and an obstructed detrusor pressure at maximum flow rate in 20/26 (77%) patients presenting with voiding LUTS. At the 6-month postoperative follow-up, 61/74 (82%) patients had marked improvement of their LUTS, SUI resolved in 39/41 (95%) patients and 1/33 (3%) patient developed de novo SUI. Preoperative DO and post-void residual urine volume were not related to the postoperative improvement, or persistence of LUTS. Meanwhile, detrusor underactivity was detected both on preoperative and postoperative UDS of 4 patients with persistent voiding LUTS. CONCLUSION: Patients had significant improvement in LUTS after POP surgery with or without an anti-incontinence procedure. Detrusor underactivity was associated with persistence of voiding LUTS. Meanwhile, preoperative DO and post-void residual urine volume were of limited prognostic value.

Holmium laser enucleation of the prostate versus bipolar transurethral enucleation of the prostate in management of benign prostatic hyperplasia: A randomized controlled trial.

OBJECTIVE: To evaluate the safety, efficacy and cost-effectiveness of holmium enucleation of the prostate and bipolar transurethral enucleation of the prostate. METHODS: In our randomized controlled trial, 120 patients were allocated into two equal groups representing holmium enucleation of the prostate and bipolar enucleation of the prostate. Operative parameters were recorded according to operative, enucleation and resection time in addition to the intraoperative complications. Patients were followed up at 1, 3 and 12 months postoperative to assess the prostate size, post-voiding residual urine, International Prostate Symptom Score, peak urine flow rate and quality of life, and compared with the preoperative parameters. Cost analysis was evaluated for both procedures. RESULTS: We evaluated 107 patients who finished our follow up and their data were analyzed. The prostate size was 135.2 ± 34.8 mL and 125 ± 26.9 mL for holmium enucleation of the prostate and bipolar enucleation of the prostate, respectively. Holmium enucleation of the prostate was associated with a shorter operative time of 83.43 ± 6.92 min compared with 94.7 ± 12.2 min in bipolar enucleation of the prostate groups. Holmium enucleation of the prostate was associated with an earlier catheter removal time and shorter hospital stay compared with bipolar enucleation of the prostate. Postoperative International Prostate Symptom Score, quality of life, post-voiding residual urine, peak urine flow rate, prostate-specific antigen and prostate volume reduction were comparable between both groups, and they both showed statistically significant improvement compared with their preoperative parameters. In the cost analysis, holmium enucleation of the prostate was more cost-effective than bipolar enucleation of the prostate. CONCLUSION: Both holmium enucleation of the prostate and bipolar enucleation of the prostate are safe and effective in the surgical management of large prostatic adenomas. Holmium enucleation of the prostate has a shorter operative time and hospital stay with earlier catheter removal time, and is more cost-effective than bipolar enucleation of the prostate.

Two-year Follow-up in Bipolar Transurethral Enucleation and Resection of the Prostate in Comparison with Bipolar Transurethral Resection of the Prostate in Treatment of Large Prostates. Randomized Controlled Trial.

OBJECTIVE: To assess the safety and long-term efficacy of bipolar transurethral enucleation and resection of the prostate (B-TUERP) in the treatment of enlarged prostate in comparison with bipolar transurethral resection of the prostate (B-TURP). MATERIALS AND METHODS: From June 2015 to March 2019, a total of 240 patients with enlarged prostates of more than 80 gm were randomized into 2 groups, each containing 120 patients. Patients in group A were subjected to B-TUERP while those in group B underwent B-TURP. The perioperative data and postoperative outcomes followed at 1, 6, and 24 months after surgery at which points they were analyzed, and a comparison made between the 2 groups. RESULTS: There were no significant differences in the preoperative parameters of the 2 groups. Comparing with B-TURP, B-TUERP had longer operative time (105.09 ± 31.08 vs 61.09 ± 29.28 min), more resected prostatic tissue (50.41 ± 13.07 vs41.12 ± 8.91 g) and had less hemoglobin drop (1.5 vs 2g/dL). In addition, indwelling catheter time, postoperative bladder irrigation duration, and hospital stay were significantly shorter in the B-TUERP group than in the B-TURP group. At 24 month after the procedure, patients with B-TUERP achieved better results of International Prostate Symptom Score (6 vs 7 P = .008), quality of life (1 vs 2, P = .243), maximal flow rate (24.9 ± 5.74 vs 20.09 ± 3.27mL/sec, P = .034), post-voiding residual urine volume (18.64 ± 3.28 vs 24.74 ± 4.02 mL, P = .001), and residual prostate volume (18.64 ± 3.28 vs 20.74 ± 4.02 mL, P < .001). On the other hand, there were no significant differences in postoperative complications between both groups. CONCLUSION: B-TUERP is a more effective modality in the treatment of enlarged prostate compared to B-TURP with almost no variation in safety.

Risk factors for the development of flank hernias and bulges following surgical flank approaches to the kidney in adults.

OBJECTIVES: To evaluate the incidence and risk factors for the development of flank incisional hernias or bulges following surgical flank approaches to the kidney. PATIENTS AND METHODS: In all, 100 consecutive adult patients who underwent variable renal surgeries via flank approaches were included in this prospective study. The incidence and risk factors for flank hernias and bulges were studied at 1- and 6-months postoperatively. RESULTS: At 6 months postoperatively, the incidence of flank bulge was 14% and for lumbar hernia was 10%. The univariate analysis showed 13 significant factors to be associated with the occurrence of a flank bulge or hernia following flank incisions. When the significant risk factors in the univariate analysis were studied by multivariate analysis, using a logistic regression analysis, four independent risk factors were identified. These were: body mass index (BMI) ≥26.3 kg/m2 (P = 0.04), the use of a self-retaining retractor during surgery (P = 0.02), not preserving or identifying the neurovascular bundle (NVB) during surgery (P = 0.028), and postoperative abdominal distention (P = 0.001). Moreover, all cases included in our study who underwent en masse wound closure, developed surgical wound infection or who had constipation developed postoperative flank bulge or hernia. CONCLUSION: High BMI, the use of self-retaining retractor, not identifying or preserving the NVB, postoperative abdominal distention, en masse wound closure, surgical wound infection, and constipation are significant risk factors associated with postoperative flank hernia and bulge.