Current Drug Discovery Technologies - Volume 18, Issue 1, 2021

Periodontal diseases are highly prevalent and can affect high percentage of the worlds’ population. Oxidative stress and inflammation play an important role in the pathogenesis of periodontal diseases. Nowadays, more attention has been focused on the herbal remedies in the field of drug discovery. Green tea is an important source of polyphenol antioxidants. It has long been used as a beverage worldwide. The most interesting polyphenol components of green tea leaves that are related with health benefits are the catechins. Taken together, this review suggested that green tea, with its wide spectrum of activities, could be a healthy alternative for controlling the damaging reactions seen in periodontal diseases.

Background: Obsessive-Compulsive Disorder (OCD) is a chronic and disabling mental disorder encountered in neurologic practice. In spite of the several classes of drugs that are available for the treatment of OCD, full remission remains challenging. Research on herbal remedies has grown over the last decade. Objective: This present review article provides information regarding the plants that exhibited protective effects on OCD. Methods: To retrieve articles related to the study, Web of Science, PubMed (NLM), Open Access Journals, LISTA (EBSCO), and Google Scholar, with keywords including Medicinal plants, Psychiatric disorders, Obsessive-compulsive disorder and Phytomedicine were used. Results: The plants which are used for the treatment of OCD are: Citrus aurantium, Crocus sativus, Benincasa hispida, Withania somnifera, Colocasia esculenta, Hypericum perforatum, Valeriana officinalis, Lagenaria siceraria and Echium amoenum. Conclusion: This review suggests that some medicinal plants can be potential drug candidates for the treatment of OCD. Aside from this, the future focus should be on the standardization of herbal extracts, and further research is required to be performed on the concept of mechanism. Clinical research in this area is in its infancy and warrants further clinical research.

Quantitative Structure–Activity Relationship (QSAR) is a popular approach developed to correlate chemical molecules with their biological activities based on their chemical structures. Machine learning techniques have proved to be promising solutions to QSAR modeling. Due to the significant role of machine learning strategies in QSAR modeling, this area of research has attracted much attention from researchers. A considerable amount of literature has been published on machine learning based QSAR modeling methodologies whilst this domain still suffers from lack of a recent and comprehensive analysis of these algorithms. This study systematically reviews the application of machine learning algorithms in QSAR, aiming to provide an analytical framework. For this purpose, we present a framework called ‘ML-QSAR‘. This framework has been designed for future research to: a) facilitate the selection of proper strategies among existing algorithms according to the application area requirements, b) help to develop and ameliorate current methods and c) providing a platform to study existing methodologies comparatively. In ML-QSAR, first a structured categorization is depicted which studied the QSAR modeling research based on machine models. Then several criteria are introduced in order to assess the models. Finally, inspired by aforementioned criteria the qualitative analysis is carried out.

Multiple sclerosis is an idiopathic and autoimmune associated motor neuron disorder that affects myelinated neurons in specific brain regions of young people, especially females. MS is characterized by oligodendrocytes destruction further responsible for demyelination, neuroinflammation, mitochondrial abnormalities, oxidative stress and neurotransmitter deficits associated with motor and cognitive dysfunctions, vertigo and muscle weakness. The limited intervention of pharmacologically active compounds like interferon-β, mitoxantrone, fingolimod and monoclonal antibodies used clinically are majorly associated with adverse drug reactions. Pre-clinically, gliotoxin ethidium bromide mimics the behavioral and neurochemical alterations in multiple sclerosis- like in experimental animals associated with the down-regulation of adenyl cyclase/cAMP/CREB, which is further responsible for a variety of neuropathogenic factors. Despite the considerable investigation of neuroprotection in curing multiple sclerosis, some complications still remain. The available medications only provide symptomatic relief but do not stop the disease progression. In this way, the development of unused beneficial methods tends to be ignored. The limitations of the current steady treatment may be because of their activity at one of the many neurotransmitters included or their failure to up direct signaling flag bearers detailed to have a vital part in neuronal sensitivity, biosynthesis of neurotransmitters and its discharge, development, and separation of the neuron, synaptic versatility and cognitive working. Therefore, the current review strictly focused on the exploration of various clinical and pre-clinical features available for multiple sclerosis to understand the pathogenic mechanisms and to introduce pharmacological interventions associated with the upregulation of intracellular adenyl cyclase/cAMP/CREB activation to ameliorate multiple sclerosis-like features.

Objectives: The goal of this article is to retrace the studies of β-D-Mannuronic Acid (M2000) as a new immunosuppressive drug with non-steroidal anti-inflammatory drugs (NSAIDs) property in miscellaneous aspects including in vitro, in vivo examinations, clinical trials and related to clinical trials studies. Our goal is to compare the effect of this drug with other similar drugs through varied researches and to follow tolerability, biocompatibility, potency, safety, and efficacy of this medication in different studies, as well as to evaluate its therapeutic effectiveness in various diseases. Materials and Methods: Different methods were applied in the studies of β-D-Mannuronic Acid under in vitro, in vivo examinations, and clinical trials phase I, II and III and related investigations to these clinical trials using different techniques showing the efficacy of this medication in the treatment of various diseases. Results: The administration of β-D-Mannuronic Acid showed the greatest tolerability and biocompatibility compared to diclofenac, piroxicam, and dexamethasone without or very low side effects. The drug has shown a punchy effect on many molecules which participate either in physiologic or in pathogenic activities in animal models and human. This new drug not only revealed the anti-inflammatory and immunosuppressive properties but also based on the results of various investigations, β-D-Mannuronic Acid showed the antidiabetic, cardioprotective and anti-tumoral effects. Conclusion: β-D-Mannuronic Acid (M2000) as a novel immunosuppressive drug with NSAID properties along with antidiabetic, cardioprotective and anti-tumoral efficacy showed great tolerability and safety profile. In addition, it has no or mild adverse events compared with many other medicines, therefore this medicament could be considered as a landmark in pharmacology and represent turn point in the treatment of different diseases based on the experimental and in vitro studies explained and clinical and related studies proved.

Objective: The present study has been carried out to evaluate the diuretic and antioxidant properties of pine herb in an animal model. Materials and Methods: 45 adult male rats were randomly divided into nine groups including: groups I (the negative control), groups II (positive control, furosemide 10 mg/kg), groups III to VIII (treatment groups received 100, 200, 400 mg/kg of the aqueous extracts of bark and fruit) and group IX received the combination of aqueous extract of bark (100 mg/kg) and the fruit (100 mg/kg). The urine output, glomerular filtration rate (GFR), electrolytes, urea, and creatinine levels were evaluated. Furthermore, the phenolic content and antioxidant activity of both extracts were also assessed using 2, 2-diphenyl-1-picrylhydrazyl (DPPH), ferric reducing antioxidant power (FRAP) and Folin-Ciocalteu methods. Results: The aqueous extracts of the pine bark and fruit increased the urinary output in a dosedependent manner. The combination of the two extracts compared to the other extracts alone significantly increased the serum potassium level. This study also showed each extract increase creatinine clearance in a dose-dependent manner (p<0.01 and p<0.05). The increase of GFR in the combination group was not significant. The current data showed a significant increase in the total phenolic content in pine bark extract in compared with the fruit extract. Conclusion: The pine bark and fruit can be useful in the prevention and treatment of kidney stones due to the high diuretic properties and antioxidant activity.

Background: Based on the encouraging results of phase III clinical trial of β-Dmannuronic acid (M2000) (as a new anti-inflammatory drug) in patients with RA, in this study, we aimed to evaluate the effects of this drug on the expression of chemokines and their receptors in PBMCs of RA patients. Methods: PBMCs of RA patients and healthy controls were separated and the patients' cells were treated with low, moderate and high doses (5, 25 and 50 μg/mL) of M2000 and optimum dose (1 μg/mL) of diclofenac, as a control in RPMI-1640 medium. Real-time PCR was used for evaluating the mRNA expression of CXCR3, CXCR4, CCR2, CCR5 and CCL2/MCP-1. Cell surface expression of CCR2 was investigated using flow cytometry. Results: CCR5 mRNA expression reduced significantly, after treatment of the patients' cells with all three doses of M2000 and optimum dose of diclofenac. CXCR3 mRNA expression was downregulated significantly followed by the treatment of these cells with moderate and high doses of M2000 and optimum dose of diclofenac. CXCR4 mRNA expression declined significantly after the treatment of these cells with moderate and high doses of M2000. CCL2 mRNA expression significantly reduced only followed by the treatment of these cells with a high dose of M2000, whereas, mRNA and cell surface expressions of CCR2 diminished significantly followed by the treatment of these cells with a high dose of M2000 and optimum dose of diclofenac. Conclusion: According to our results, M2000 through the down-regulation of chemokines and their receptors may restrict the infiltration of immune cells into the synovium.

Background: Epidermal growth factor receptor (EGFR, ErBb) belongs to family of receptor tyrosine kinase (RTKs) that plays an important role in multiple cell signaling pathways, which includes cell growth, multiplication apoptosis, etc. Overexpression of EGFR results in development of malignant cells. Therefore, EGFR is considered one of the important target for cancer therapy. Objective: In this study, virtual screening of 329 flavonoids obtained from the Naturally Occurring Plant-based Anti-cancer Compound-Activity-Target (NPACT) database had been performed to identify novel EGFR inhibitors. Materials and Methods: Virtual screening of flavonoids were carried out using different in silico methods, which includes molecular docking studies, prediction of druglikeness, in silico toxicity studies and bioactivity prediction. Results: Six flavonoids NPACT00061, NPACT00062, NPACT00066, NPACT00280, NPACT00700 and NPACT00856 were identified as potential EGFR inhibitors with good docking score and druglikeness properties. In the in silico toxicity studies, compound NPACT00061, NPACT00062, NPACT00066 and NPACT00856 were found to be carcinogenic. Finally, two flavonoids NPACT00280 and NPACT00700 were recognized as novel EGFR inhibitors. Conclusion: Our findings suggest that compound NPACT00280 and NPACT00700 could be further explored as novel EGFR inhibitors.

Objectives: Quantitative structure activity relationship (QSAR) was used to study the partition coefficient of some quinolones and their derivatives. Methods: These molecules are broad-spectrum antibiotic pharmaceutics. First, data were divided into two categories of train and test (validation) sets using a random selection method. Second, three approaches, including stepwise selection (STS) (forward), genetic algorithm (GA), and simulated annealing (SA) were used to select the descriptors, to examine the effect feature selection methods. To find the relation between descriptors and partition coefficient, multiple linear regression (MLR), principal component regression (PCR) and partial least squares (PLS) were used. Results: QSAR study showed that both regression and descriptor selection methods have a vital role in the results. Different statistical metrics showed that the MLR-SA approach with (r2=0.96, q2=0.91, pred_r2=0.95) gives the best outcome. Conclusion: The proposed expression by the MLR-SA approach can be used in the better design of novel quinolones and their derivatives.

Background: Purified fractions from a Boswellia serrata Roxb. Ex. Colebr. (Burseraceae) extract (ETOH and DCM) contain biologically active compounds that are well known for having inflammation inhibitory properties. In this work, the purified fractions were tested in-vitro for LTC4, LTA4 and COX-2 activities using ELISA and qPCR was performed to determine gene regulation in human leukemia (HL-60) Cells. Two D-imaging tomography was performed to determine the anti-inflammatory activities of the fractions in BALB/c mouse model of lung inflammation. Objective: To evaluate anti-inflammatory activities of bioactive compounds of Boswellia serrata purified fractions. Methods: In-vitro MTT assay was performed in HL-60 cell lines for measuring the toxicity/ viability of the cells. ELISA tests were performed for evaluating LTA4, LTC4 and COX-2 activities. qPCR was performed to evaluate the expression of mRNA in HL-60 cells. In-vivo experiments were performed in OVA sensitized and challenged BALB/c mice at two doses of Boswellia serrata purified fraction containing 6% Boswellic acid of 50 and 100mg/kg body weight were given orally and the standard drug dexamethasone (DXA, 4 mg/kg body weight) and reduction in lung inflammation was assessed by using an IVIS Xenogen in-vivo fluorescence imaging system. Results: A purified fraction of Boswellia serrata ETOH extracts reduced leukotriene-C4-synthase activity by 52%, leuktotriene-A4-hydrolase activity by 22% and COX-2 activity by 99% with an IC50 of 12.5μg/ml. Intragastric administration of the purified fraction of Boswellia serrata at two doses of 50mg/kg b.w. and 100mg/kg b.w., respectively along with 2-3% HPMC resulted in a ∼51% (P value <0.01) reduction in OVA induced lung inflammation in BALB/c mice as observed by imaging tomography. Treatment of the OVA challenged mice with standard drug dexamethasone (DXA) reduced inflammation by ∼66% with significant value (P<0.0001). Conclusion: The present study describes that Boswellia serrata ethanolic extracts purified fraction (ETOH-BS) possess significant anti-inflammatory activities in HL-60 and in BALB/c and further supports for its use as Ayurvedic medicines traditionally in the treatment of lung disorders including allergy and asthma.

Aims: To identify natural inhibitors against MCT8 for Allan-Herndon-Dudley Syndrome. Background: Monocarboxylate Transporter 8 (MCT8) is a Thyroid Hormone (TH) transporter which is highly expressed in the liver and brain. Mutations in the MCT8 gene (SLC16A2) cause a syndrome of psychomotor retardation in humans, known as Allan-Herndon-Dudley syndrome (AHDS). Currently, no treatment is available for AHDS. Therefore, there is a need to discover new inhibitors of MCT8 for treating AHDS. Objective: Considering the importance of natural compounds in drug discovery, this study aimed to identify potential natural inhibitors against MCT8. Methods: As Protein-ligand interactions play a key role in structure based drug design, this study screened 24 natural kinase inhibitors and investigated their binding affinity against MCT8 by using molecular docking. The modelled 3D structure of MCT8 docked with 24 compounds using PyRX through Autodock Vina. Drug-likeness studies were made using Swiss ADME and Lipinski’s rule of five was performed. Triac, desipramine and silychristin were used as the positive controls. Binding energies of the selected compounds were compared with that of positive controls. Result: The results showed that emodin exhibited best binding energy of -8.6 kcal/mol followed by helenaquinol, cercosporamide and resveratrol. Moreover, it was observed that emodin and helenaquinol exhibit higher binding energy than the positive controls. Cercosporamide and resveratrol exhibited higher binding energy than triac and desipramine and showed the binding energy similar to silychristin. Conclusion: This study reveals that these compounds could be promising candidates for further evaluation for AHDS prevention.

Background: Ulcerative Colitis (UC) is a chronic condition that represents a group of intestinal disorders causing prolonged inflammation of the digestive tract. Nowadays, efforts to investigate new remedies have led to a committed movement toward the integration of traditional and complementary medicine into mainstream medicine. In Traditional Persian Medicine (TPM), Maqliasa is one of the most frequent gastrointestinal prescriptions which is claimed to be effective in both remission and recurrent phases of UC. Objective: The aim of this pilot study was to examine the effect of Maqliasa on UC symptoms. Methods: Through a non-randomized before-after uncontrolled clinical trial, 13 outpatients with active UC were enrolled in the study. They continued their conventional drug regimens plus Maqliasa capsules (2 capsules t.i.d.) for 28 days. Three visits were arranged for each patient− the first admission, day 14^th admission and day 28^th admission. The patients were evaluated by Lichtiger Colitis Activity Index. Wilcoxon signed-rank test was used for statistical analysis. Results: The Lichtiger colitis activity index improved in the study group was compared to the corresponding baseline values: baseline score: 7.8 ± 0.5; after two weeks: 5.9 ± 0.6 (P=0.002); after four weeks: 3.6 ± 0.5 (P=0.001). Conclusions: This study showed the promising effect of Maqliasa in the treatment of active UC. However, due to some of the limitations of the study, conducting future high-quality randomized clinical trials would be crucial.

Aims: The aim of present investigation was to evaluate the traditional claim of Ficus retusa as an anti-diarrheal and anti-spasmodic agent using different pharmacological models. Background: Diarrhea is considered as major cause of mortality, especially in children and aged persons. Because of diarrhoea, 17% of admitted children get die. In order to treat the diarrhea, natural drugs may be useful. Objective: In order to prove the traditional claim of Ficus retusa, present work was undertaken with objective to prove antidiarrheal and antispasmodic activity. Methods: The anti-diarrhoeal activity was evaluated by magnesium sulphate induced diarrhea and 5-hydroxy tryptamine(5HT) induced diarrhea. Further, the exact were subjected to gastrointestinal motility test using standard procedure. Result: Finding of the present study suggested that significant response was exhibited by ethanolic extract (400mg/kg bw.) of Ficus retusa. Conclusion: The response towards bioactivity was dose dependent. It was concluded that 400mg/kg bw of ethanolic extract is most potent in antidiarrhoeal and antispasmodic activity.

Aims: To fetch pathways involved in targetting Hsp90 through Curcumin and Epigallocatechin through Network pharmacological approach. Background: Hsp90 is a molecular chaperone involved in stabilizing inflammatory protein which may lead to chronic diseases. The herbal compounds Curcumin and Epigallocatechin processing antiinflammatory properties are known to follow a common pathway and control the expression of Hsp90. Objective: To collect the gene targets of Hsp90, Curcumin and Epigallocatechin in order to understand protein-protein interactions of gene targets by constructing the interactome to identify the hub proteins. Hub proteins docking was performed with curcumin and epigallocatechin. Finally, hub proteins involvement with various human diseases were identified. Methods: The gene targets of Hsp90, Curcumin and Epigallocatechin were obtained from there respective databases. Protein-protein interactions of Pkcδ-Nrf2 and Tlr4 pathway gene targets were collected from String database. Protein interaction network was constructed and merged to get intercession network in cytoscape and Cluego was used to predict the disease related target genes. Docking of ligands to target proteins was carried out using Autodock vina tool. Result: The main key regulators of Curcumin and Epigallocatechin were identified particularly from Pkcδ-Nrf2 and Tlr4 pathway. Conclusion: The combined action of Curcumin and Epigallocatechin can reduce the expression of Hsp90 eventually controlling the inflammation.

Aims: In the presented work we successfully discovered several novel NQO1 inducers using the computational approaches. Background: The phytochemical sulforaphane (SFN) is a potent inducer of carcinogen detoxication enzymes like NAD(P)H:quinone oxidoreductase 1 (NQO1) through the Kelch-like erythroid cellderived protein with CNC homology[ECH]-associated protein 1 (Keap1)-[NF-E2]-related factor 2 (Nrf2) signaling pathway. Objective: In this paper, we report the first QSAR and pharmacophore modeling study of sulforaphane analogues as NQO1 inducers. The pharmacophore model and understanding the relationships between the structures and activities of the known inducers will give useful information on the structural basis for NQO1 enzymatic activity and lead optimization for future rational design of new sulforaphane analogues as potent NQO1 inducers. Methods: In this study, a combination of QSAR modeling, pharmacophore generation, virtual screening and molecular docking was performed on a series of sulforaphane analogues as NQO1 inducers. Results: In deriving the QSAR model, the stepwise multiple linear regression established a reliable model with the training set (N: 43, R: 0.971, RMSE: 0.216) and test set (N: 14, R: 0.870, RMSE: 0.324, Q2: 0.80) molecules. The best ligand-based pharmacophore model comprised two hydrophobic (HY), one ring aromatic (RA) and three hydrogen bond acceptor (HBA) sites. The model was validated by a testing set and the decoys set, Güner-Henry (GH) scoring methods, etc. The enrichment of model was assessed by the sensitivity (0.92) and specificity (0.95). Moreover, the values of enrichment factor (EF) and the area under the receiver operating characteristics curve (AUC) were 12 and 0.94, respectively. This well-validated model was applied to screen two Asinex libraries for the novel NQO1 inducers. The hits were subsequently subjected to molecular docking after being filtering by Lipinski’s, MDDR-like, and Veber rules as well as evaluating their interaction with three major drugmetabolizing P450 enzymes, CYP2C9, CYP2D6 and CYP3A4. Ultimately, 12 hits filtered by molecular docking were subjected to validated QSAR model for calculating their inducer potencies and were introduced as potential NQO1 inducers for further investing action. Conclusion: Conclusively, the validated QSAR model was applied on the hits to calculate their inducer potencies and these 12 hits were introduced as potential NQO1 inducers for further investigations.