Mizied Falah

Indexing molecules for their hERG liability

The human Ether-a-go-go-Related-Gene (hERG) potassium (K(+)) channel is liable to drug-inducing blockage that prolongs the QT interval of the cardiac action potential, triggers arrhythmia and possibly causes sudden cardiac death. Early prediction of drug liability to hERG K(+) channel is therefore highly important and preferably obligatory at earlier stages of any drug discovery process. In vitro assessment of drug binding affinity to hERG K(+) channel involves substantial expenses, time, and labor; and therefore computational models for predicting liabilities of drug candidates for hERG toxicity is of much importance. In the present study, we apply the Iterative Stochastic Elimination (ISE) algorithm to construct a large number of rule-based models (filters) and exploit their combination for developing the concept of hERG Toxicity Index (ETI). ETI estimates the molecular risk to be a blocker of hERG potassium channel. The area under the curve (AUC) of the attained model is 0.94. The averaged ETI of hERG binders, drugs from CMC, clinical-MDDR, endogenous molecules, ACD and ZINC, were found to be 9.17, 2.53, 3.3, -1.98, -2.49 and -3.86 respectively. Applying the proposed hERG Toxicity Index Model on external test set composed of more than 1300 hERG blockers picked from chEMBL shows excellent performance (Matthews Correlation Coefficient of 0.89). The proposed strategy could be implemented for the evaluation of chemicals in the hit/lead optimization stages of the drug discovery process, improve the selection of drug candidates as well as the development of safe pharmaceutical products.

Nature is the best source of anticancer drugs: Indexing natural products for their anticancer bioactivity

Cancer is considered one of the primary diseases that cause morbidity and mortality in millions of people worldwide and due to its prevalence, there is undoubtedly an unmet need to discover novel anticancer drugs. However, the traditional process of drug discovery and development is lengthy and expensive, so the application of in silico techniques and optimization algorithms in drug discovery projects can provide a solution, saving time and costs. A set of 617 approved anticancer drugs, constituting the active domain, and a set of 2,892 natural products, constituting the inactive domain, were employed to build predictive models and to index natural products for their anticancer bioactivity. Using the iterative stochastic elimination optimization technique, we obtained a highly discriminative and robust model, with an area under the curve of 0.95. Twelve natural products that scored highly as potential anticancer drug candidates are disclosed. Searching the scientific literature revealed that few of those molecules (Neoechinulin, Colchicine, and Piperolactam) have already been experimentally screened for their anticancer activity and found active. The other phytochemicals await evaluation for their anticancerous activity in wet lab.

Indexing Natural Products for Their Potential Anti-Diabetic Activity: Filtering and Mapping Discriminative Physicochemical Properties

Diabetes mellitus (DM) poses a major health problem, for which there is an unmet need to develop novel drugs. The application of in silico techniques and optimization algorithms is instrumental to achieving this goal. A set of 97 approved anti-diabetic drugs, representing the active domain, and a set of 2892 natural products, representing the inactive domain, were used to construct predictive models and to index anti-diabetic bioactivity. Our recently-developed approach of ‘iterative stochastic elimination’ was utilized. This article describes a highly discriminative and robust model, with an area under the curve above 0.96. Using the indexing model and a mix ratio of 1:1000 (active/inactive), 65% of the anti-diabetic drugs in the sample were captured in the top 1% of the screened compounds, compared to 1% in the random model. Some of the natural products that scored highly as potential anti-diabetic drug candidates are disclosed. One of those natural products is caffeine, which is noted in the scientific literature as having the capability to decrease blood glucose levels. The other nine phytochemicals await evaluation in a wet lab for their anti-diabetic activity. The indexing model proposed herein is useful for the virtual screening of large chemical databases and for the construction of anti-diabetes focused libraries.

Nature is the best source of anti-inflammatory drugs: indexing natural products for their anti-inflammatory bioactivity

ObjectivesThe aim was to index natural products for less expensive preventive or curative anti-inflammatory therapeutic drugs.MaterialsA set of 441 anti-inflammatory drugs representing the active domain and 2892 natural products representing the inactive domain was used to construct a predictive model for bioactivity-indexing purposes.MethodThe model for indexing the natural products for potential anti-inflammatory activity was constructed using the iterative stochastic elimination algorithm (ISE). ISE is capable of differentiating between active and inactive anti-inflammatory molecules.ResultsBy applying the prediction model to a mix set of (active/inactive) substances, we managed to capture 38% of the anti-inflammatory drugs in the top 1% of the screened set of chemicals, yielding enrichment factor of 38. Ten natural products that scored highly as potential anti-inflammatory drug candidates are disclosed. Searching the PubMed revealed that only three molecules (Moupinamide, Capsaicin, and Hypaphorine) out of the ten were tested and reported as anti-inflammatory. The other seven phytochemicals await evaluation for their anti-inflammatory activity in wet lab.ConclusionThe proposed anti-inflammatory model can be utilized for the virtual screening of large chemical databases and for indexing natural products for potential anti-inflammatory activity.

Storage effect on viability and biofunctionality of human adipose tissue-derived stromal cells.

BACKGROUND AIMS In our recent studies, the transplantation of human adipose tissue-derived stromal cells (ASCs) has shown promise for treatment of diseases related to bone and joint disorders. METHODS For the current clinical applications, ASCs were formulated and suspended in PlasmaLyte A supplemented with heparin, glucose and human serum albumin, balanced to pH 7.4 with sodium bicarbonate. This cell solution constitutes 20% of the overall transplanted mixture and is supplemented with hyaluronic acid (60%) and OraGraft particles (20%). We intended to investigate the effect of this transplantation mixture on the viability and biofunctionality of ASCs in bone formation. Freshly harvested cells were resuspended and incubated in the indicated mixture for up to 48 h at 4°C. Cell viability was assessed using trypan blue and AlamarBlue, and cell functionality was determined by quantifying their adhesion rate in vitro and bone formation in an ectopic mouse model. RESULTS More than 80% of the ASCs stored in the transplantation mixture were viable for up to 24 h. Cell viability beyond 24 h in storage decreased to approximately 50%. In addition, an equal degree of bone formation was observed between the cells transplanted following incubation in transplantation mixture for up to 24 h and zero-time non-incubated cells (control). CONCLUSIONS The viability and functionality of ASCs stored in the presented formulation will make such cell therapy accessible to larger and more remote populations.

A simple approach discriminating cardio-safe drugs from toxic ones.

More than 130 FDA-approved drugs have been identified for now to prolong the QT interval and possibly lead to sudden cardiac death. Due to their toxic effect, some of these drugs have been withdrawn from the pharmaceutical market. In this study, we have formulated few rules to assess the ability to prolong QT interval and thereby discriminate between cardiotoxic and -safe drugs. These rules have clearly determined that cardio-toxic drugs are more likely to obey Lipinski rule of 5 and Oprea lead-like rule. Moreover, the cardio-toxic drugs have been found to have in common values of -0.5 to 6.5 log P, 1-5 nitrogen atoms, up to 4 oxygen atoms, 5-27 hydrophobic atoms, and 15-53 single bonds. Matthews Correlation Coefficient with the value of 0.6 was also attained and nearly 96% of the cardio-toxic drugs were successfully covered. Thus, despite the simplicity of this methodology, we have obtained interesting and informative results. The proposed set of these simple rules could be employed to infer cardio-toxicity or -safety for current and potential drugs. The present study will have important impact on decision making in the fields of drug development, molecule screening in biological assays, and other applications as well.

An ECM-Mimicking, Mesenchymal Stem Cell-Embedded Hybrid Scaffold for Bone Regeneration

While biologically feasible, bone repair is often inadequate, particularly in cases of large defects. The search for effective bone regeneration strategies has led to the emergence of bone tissue engineering (TE) techniques. When integrating electrospinning techniques, scaffolds featuring randomly oriented or aligned fibers, characteristic of the extracellular matrix (ECM), can be fabricated. In parallel, mesenchymal stem cells (MSCs), which are capable of both self-renewing and differentiating into numerous tissue types, have been suggested to be a suitable option for cell-based tissue engineering therapies. This work aimed to create a novel biocompatible hybrid scaffold composed of electrospun polymeric nanofibers combined with osteoconductive ceramics, loaded with human MSCs, to yield a tissue-like construct to promote in vivo bone formation. Characterization of the cell-embedded scaffolds demonstrated their resemblance to bone tissue extracellular matrix, on both micro- and nanoscales and MSC viability and integration within the electrospun nanofibers. Subcutaneous implantation of the cell-embedded scaffolds in the dorsal side of mice led to new bone, muscle, adipose, and connective tissue formation within 8 weeks. This hybrid scaffold may represent a step forward in the pursuit of advanced bone tissue engineering scaffolds.

Use of buccal fat pad for closure of perforation and graft material in a maxillary sinus elevation procedure: A preliminary study

PURPOSE Maxillary sinus membrane elevation is a common procedure intended to increase the volume of the maxillary sinus osseous floor prior to insertion of dental implants. The aim of this study was to evaluate bone formation under a perforated sinus membrane grafted with buccal fat pad (BFP). MATERIALS AND METHODS Six consecutive patients (10 sinus augmentations, 24 dental implants) underwent sinus floor elevation, using the lateral window approach. The compartment around the implants under the sinus mucosal lining in the sinus floor was filled with adipose tissues, which were retrieved as free graft from BFP. Clinical and radiologic follow-up was conducted through the healing period; in all cases, samples were taken for biopsy during the stage-two surgery. RESULTS New bone consolidation in the maxillary sinus was radiologically and histologically observed within an average of 7.2 months after the sinus augmentation. According to the histomorphometric data, 62.8% ± 13.1% vital bone formation was observed. Out of the 24 implants placed, only 1 failed, indicating a 95% overall implant survival rate. CONCLUSION Despite the limited size of this case series, BFP can be considered an autologous osteogenic graft material and/or biologic membrane capable of achieving high success rates in sinus elevation procedures.

Raised Schneiderian membrane compared with peeled bony walls in the formation of bone.

andible.2 The symptoms of neuropathy of the chin are also imilar symptoms of Vincent’s disease, which occurs in cases f osteomyelitis of the jaw. We describe a rare case of bisphosphonate-related steomyelitis, or osteonecrosis of the jaw, or both BROMJ/BRONJ), and methotrexate-associated lymphoproiferative disorder in the left posterior mandible. It was ifficult to diagnose, because the initial manifestation of the europathy could have been a combination of numb chin yndrome and Vincent disease. A 66-year-old woman was referred to our department with umbness and swelling of the left mandible in January 2015. er symptoms had begun 2 months before when she had had eeth extracted and had taken antibiotics for osteomyelitis. er medical history included rheumatoid arthritis and osteoorosis. She had been taking methotrexate (8 mg/week) for years, and alendronate sodium hydrate (35 mg/week) for 8 onths. There was exposed bone at the site of the extraction nd healing was prolonged (Fig. 1). Computed tomograhy showed osteosclerosis, with a suspected diagnosis of ROMJ/BRONJ, so she was immediately given antibiotics ntravenously. We did not biopsy the wound, because expoure of the bones of the jaw should be avoided in cases of RONJ.3 We found lactate dehydrogenase concentrations of 036 IU/L (isozyme2: 48%, isozyme3: 28%). Bone marrow spiration showed no tumour cells. Finally, biopsy examinaion of the stomach showed diffuse large B-cell lymphoma. ositron emission tomography showed increased uptake in he right kidney, the pancreas, stomach, falx cerebri, in all ones, and in the lymph nodes of the lower left side of the andible. S