Integrated computational approach toward discovery of multi-targeted natural products from Thumbai (Leucas aspera) for attuning NKT cells.

A multi-omics-based approach targeting the plant-based natural products from Thumbai (Leucas aspera), an important yet untapped potential source of many therapeutic agents for myriads of immunological conditions and genetic disorders, was conceptualized to reconnoiter its potential biomedical application. A library of 79 compounds from this plant was created, out of which 9 compounds qualified the pharmacokinetics parameters. Reverse pharmacophore technique for target fishing of the screened compounds was executed through which renin receptor (ATP6AP2) and thymidylate kinase (DTYMK) were identified as potential targets. Network biology approaches were used to comprehend and validate the functional, biochemical and clinical relevance of the targets. The target-ligand interaction and subsequent stability parameters at molecular scale were investigated using multiple strategies including molecular modeling, pharmacophore approaches and molecular dynamics simulation. Herein, isololiolide and 4-hydroxy-2-methoxycinnamaldehyde were substantiated as the lead molecules exhibiting comparatively the best binding affinity against the two putative protein targets. These natural lead products from L. aspera and the combinatorial effects may have plausible medical applications in a wide variety of neurodegenerative, genetic and developmental disorders. The lead molecules also exhibit promising alternative in diagnostics and therapeutics through immuno-modulation targeting natural killer T-cell function in transplantation-related pathogenesis, autoimmune and other immunological disorders.Communicated by Ramaswamy H. Sarma.

Network pharmacology based high throughput screening for identification of multi targeted anti-diabetic compound from traditionally used plants.

The incurable Type 2 diabetes mellitus (T2DM) has now been considered a pandemic with only supportive care in existence. Due to the adverse effects of available anti-diabetic drugs, there arises a great urgency to develop new drug molecules. One of the alternatives that can be considered for the treatment of T2DM are natural compounds from traditionally used herbal medicine. The present study undertakes, an integrated multidisciplinary concept of Network Pharmacology to evaluate the efficacy of potent anti-diabetic compound from traditionally used anti-diabetic plants of north east India and followed by DFT analysis. In the course of the study, 22 plant species were selected on the basis of their use in traditional medicine for the treatment of T2DM by various ethnic groups of the north eastern region of India. Initially, a library of 1053 compounds derived from these plants was generated. This was followed by network preparation between compounds and targets based on the docking result. The compounds having the best network property were considered for DFT analysis. We have identified that auraptene, a monoterpene coumarin for its activity in the management of Type 2 diabetes mellitus and deciphered its unexplored probable mechanisms. Molecular dynamics simulation of the ligand-protein complexes also reveals the stable binding of auraptene with the target proteins namely, Protein Kinase C θ, Glucocorticoid receptor, 11-ß hydroxysteroid dehydrogenase 1 and Aldose Reductase, all of which form uniform interactions throughout the MD simulation trajectory. Therefore, this finding could provide new insights for the development of a new anti-diabetic drug.Communicated by Ramaswamy H. Sarma.

Synthesis and biological evaluation of novel 1,2,3-triazole derivatives as anti-tubercular agents.

A library of seventeen novel 1,2,3-triazole derivatives were efficiently synthesized in excellent yields by the popular 'click chemistry' approach and evaluated in vitro for their anti-tubercular activity against Mycobacterium tuberculosis H37Ra (ATCC 25177 strain). Among the series, six compounds exhibited significant activity with minimum inhibitory concentration (MIC) values ranging from 3.12 to 0.78µg/mL and along with no significant cytotoxicity against MBMDMQs (mouse bone marrow derived macrophages). Molecular docking of the target compounds into the active site of DprE1 (Decaprenylphosphoryl-ß-d-ribose-2'-epimerase) enzyme revealed noteworthy information on the plausible binding interactions.

Identification of novel human renin inhibitors through a combined approach of pharmacophore modelling, molecular DFT analysis and in silico screening.

Renin is an aspartyl protease of the renin-angiotensin system (RAS) and the first enzyme of the biochemical pathway for the generation of angiotensin II - a potent vasoconstrictor involved in the maintenance of cardiovascular homeostasis and the regulation of blood pressure. High enzymatic specificity of renin and its involvement in the catalysis of the rate-limiting step of the RAS hormone system qualify it as a good target for inhibition of hypertension and other associated diseases. Ligand-based pharmacophore model (Hypo1) was generated from a training set of 24 compounds with renin inhibitory activity. The best hypothesis consisted of one Hydrogen Bond Acceptor (HBA), three Hydrophobic Aliphatic (HY-Al) and one Ring Aromatic (AR) features. This well-validated pharmacophore hypothesis (correlation coefficient 0.95) was further utilized as a 3D query to screen database compounds, which included structures from two natural product repositories. These screened compounds were further analyzed for drug-likeness and ADMET studies. The compounds which satisfied the qualifying criteria were then subjected to molecular docking and Density Functional Theory (DFT) analysis in order to discern their atomic level interactions at the active site of the 3D structure of rennin. The pharmacophore-based modelling that has been used to generate the novel findings of the present study would be an avant-garde approach towards the development of potent inhibitors of renin.

Network pharmacology-based virtual screening of natural products from Clerodendrum species for identification of novel anti-cancer therapeutics.

Plant-derived natural products (NPs) play a vital role in the discovery of new drug molecules and these are used for development of novel therapeutic drugs for a specific disease target. Literature review suggests that natural products possess strong inhibitory efficacy against various types of cancer cells. Clerodendrum indicum and Clerodendrum serratum are reported to have anticancer activity; therefore a study was carried out to identify selective anticancer agents from these plants species. In this report, we employed a docking weighted network pharmacological approach to understand the multi-therapeutics potentiality of C. indicum and C. serratum against various types of cancer. A library of 53 natural products derived from these plants was compiled from the literature and three dimensional space analyses were performed in order to establish the drug-likeness of the NPs library. Further, an NPs-cancer network was built based on docking. We predicted five compounds, namely apigenin 7-glucoside, hispidulin, scutellarein-7-O-beta-d-glucuronate, acteoside and verbascoside, to be potential binding therapeutics for cancer target proteins. Apigenin 7-glucoside and hispidulin were found to have maximum binding interactions (relationship) with 17 cancer drug targets in terms of docking weighted network pharmacological analysis. Hence, we used an integrative approach obtained from network pharmacology for identifying combinatorial drug actions against the cancer targets. We believe that our present study may provide important clues for finding novel drug inhibitors for cancer.

Novel butyrylcholinesterase inhibitors through pharmacophore modeling, virtual screening and DFT-based approaches along-with design of bioisosterism-based analogues.

Ligand and structure-based pharmacophore models were used to identify the important chemical features of butyrylcholinesterase (BChE) inhibitors. A training set of 16 known structurally diverse compounds with a wide range of inhibitory activity against BChE was used to develop a quantitative ligand-based pharmacophore (Hypo1) model to identify novel BChE inhibitors in virtual screening databases. A structure-based pharmacophore hypothesis (Phar1) was also developed with the ligand-binding site of BChE in consideration. Further, the models were validated using test set, Fisher's Randomization and Leave-one-out validation methods. Well-validated pharmacophore hypotheses were further used as 3D queries in virtual screening and 430 compounds were finally selected for molecular docking analysis. Subsequently, ADMET, DFT and chemical similarity search were employed to narrow down on seven compounds as potential drug candidates. Analogues of the best hit were further developed through a bioisosterism-guided approach to further generate a library of potential BChE inhibitors.

3D pharmacophore-based virtual screening, docking and density functional theory approach towards the discovery of novel human epidermal growth factor receptor-2 (HER2) inhibitors.

Human epidermal growth factor receptor 2 (HER2) is one of the four members of the epidermal growth factor receptor (EGFR) family and is expressed to facilitate cellular proliferation across various tissue types. Therapies targeting HER2, which is a transmembrane glycoprotein with tyrosine kinase activity, offer promising prospects especially in breast and gastric/gastroesophageal cancer patients. Persistence of both primary and acquired resistance to various routine drugs/antibodies is a disappointing outcome in the treatment of many HER2 positive cancer patients and is a challenge that requires formulation of new and improved strategies to overcome the same. Identification of novel HER2 inhibitors with improved therapeutics index was performed with a highly correlating (r=0.975) ligand-based pharmacophore model (Hypo1) in this study. Hypo1 was generated from a training set of 22 compounds with HER2 inhibitory activity and this well-validated hypothesis was subsequently used as a 3D query to screen compounds in a total of four databases of which two were natural product databases. Further, these compounds were analyzed for compliance with Veber's drug-likeness rule and optimum ADMET parameters. The selected compounds were then subjected to molecular docking and Density Functional Theory (DFT) analysis to discern their molecular interactions at the active site of HER2. The findings thus presented would be an important starting point towards the development of novel HER2 inhibitors using well-validated computational techniques.

An In Silico Approach for Identification of Potential Anti-Mycobacterial Targets of Vasicine and Related Chemical Compounds.

Tuberculosis (TB) is known to mankind as one of the most pervasive and persistent of diseases since the early days of civilization. The growing resistance of the causative pathogen Mycobacterium tuberculosis to the standard drug regimen for TB poses further difficulty in its treatment and control. Screening of novel plant-derived compounds with promising anti-tubercular activity has been cited as a prospective route for new anti-tubercular drug discovery and design. Justicia adhatoda L. is a perennial evergreen shrub which is widely mentioned in scientific literature on account of its potent anti-mycobacterial properties. In the present study, we have employed a series of computational methodologies to reveal the probable molecular interactions of vasicine, the principal alkaloid of Justicia adhatoda L., and two of its close natural derivatives- vasicinone and deoxyvasicine, with certain biological targets in M. tuberculosis. Targets were identified from literature and through a reverse Pharmacophore-based approach. Subsequent comparative molecular docking to identify the best ligand-target interactions revealed Antigen 85C of M. tuberculosis as the most potent biological target of vasicine on the basis of optimum molecular docking values. A chemogenomics approach was also employed to validate the molecular interactions between the same class of chemical compounds as vasicine and Antigen 85C. Further, a library of structural analogs of vasicine was created by bioiosterism-based drug design to identify structural analogs with better inhibitory potential against Antigen 85C.

Virtual Screening of compounds from Tabernaemontana divaricata for potential anti-bacterial activity.

Virtual Screening and Molecular Docking analysis for Tabernaemontana divaricata derived 66 Law Molecular Weight Compounds (LMW) was conducted and to identified and predicted novel molecules as a inhibitor of Streptococcus pneumonia. The investigation has revealed several compounds with optimum binding towards Penicillin-binding proteins, Sialidases, Aspartate betasemialdehide dehydrogenase cell membrane protein of Streptococcus pneumonia. Docking results were computed in term of binding energy, ligand efficiency and number of hydrogen bonding. Apparicine (-5.14), 5-Hydroxyvoaphylline (-4.78), Voacangine (-4.7), 19-Hydroxycoronaridine (-4.44) and Coronaridine (-4.72) are identified as most suitable to bind with N-acetylglucosamine-1- phosphate uridyltransferase receptor. Ervaticine (-6.33), Ibogamine (-6.15), Methylvoaphylline (-5.74) and Coronaridine hydroxyindolenine (-5.32) has showed novel binding against the penicillin-binding proteins. Ervaticine (-6.42), 5-oxo-11-hydroxy voaphylline (-6.18), Conolobine B (-6.02) has found optimum binding against the active site of NanB sialidase of Streptococcus pneumonia. The compounds 3S-Cyanocoronaridine (-6.71), 19-Epivoacristine (-5.48) and Ervaticine(-5.45) interacting with aspartate beta-semialdehide and found suitable with least docking score.

Design of inhibitors of the HIV-1 integrase core domain using virtual screening.

Acquired immunodeficiency syndrome (AIDS) is a disease of the human immune system caused by the human immunodeficiency virus (HIV). The integrase (IN) enzyme of HIV interacts with several cellular and viral proteins during the integration process. Thus, it represents an appropriate target for antiretroviral drugs (ARVs). We performed virtual screening of database compounds and designed analogues using Elvitegravir (EVG) as a standard compound. The 378 screened compounds were retrieved from ZINC, ChemSpider, PubChem, and ChemBank Chemical Databases based on chemical similarity and literature searches related to the structure of EVG. The Physiochemical properties, Bioactivity, Toxicity and Absorption, Distribution, Metabolism and Excretion of Molecules (ADME) of these compounds were predicted and docking Experiments were conducted using Molegro Virtual Docker software. The docking and ADME suggested very significant results in regard to EVG. The MolDock and Rerank scores were used to analyze the results. The compounds ZINC26507991 (-84.22), Analogue 9 (-68.49), ZINC20731658 (-66.79), ZINC00210363 (-43.44) showed better binding orientation with IN receptor model with respect to EVG (182.52). The ZINC26507991 has showed significant ADME result.

Draft Genome Sequence of Pseudomonas aeruginosa Strain N002, Isolated from Crude Oil-Contaminated Soil from Geleky, Assam, India.

Here, we report the draft genome sequence of crude oil-degrading Pseudomonas aeruginosa strain N002, isolated from a crude oil-polluted soil sample from Geleky, Assam, India. Multiple genes potentially involved in crude oil degradation were identified.

Insights from the docking analysis of biologically active compounds from plant Litsea Genus as potential COX-2 inhibitors.

Litsea spp of Laural family are traditionally used as herbal medicine for treating inflammation including gastroenterologia, oedema and rheumatic arthritis. Therefore, it is of interest to investigate and understand the molecular principles for such actions. Here, we have illustrated the binding of thirteen Litsea derived biologically active compounds against the inflammation associated target COX (cyclo-oxygenase) -2 enzymes. We compared the binding information of these compounds with a selected number of already known COX-2 inhibitors. The comparison reflected that some of these compounds such as linderol, catechin, 6'-hydroxy-2',3',4' - trimethoxy-chalcone and litseaone have better or equivalent binding features compared to already known inhibitory compounds namely celecoxib, acetylsalicylic acid, rofecoxib. Therefore, all these small compounds reported from plant Litsea spp were found to possess potential medicinal values with anti-inflammatory properties.

Adrenal rest in testis diagnosed by fine-needle aspiration cytology.

In this article, we have described an extremely uncommon entity of adrenal rest in testis in fine-needle aspiration cytology in a 7-year-old male child with symptoms of precocious puberty. The patient had a raised serum testosterone level along with a well-defined solitary mass in the testis. Fine-needle aspiration cytology smears show a dispersed population of large cells with abundant finely granular cytoplasm, eccentric nuclei, coarse nuclear chromatin, and multiple prominent nucleoli. Considering the clinical, radiological, biochemical, and also cytological features, a diagnosis of adrenal cell rest was made.

Primary leiomyosarcoma of the prostate with lung metastasis: report of a case diagnosed by fine-needle aspiration cytology.

Prostate leiomyosarcoma is an extremely rare and highly aggressive neoplasm that accounts for less than 0.1% of primary prostate malignancies. Herein, we present a patient with primary leiomyosarcoma of the prostate with lung metastasis diagnosed primarily on fine-needle aspiration cytology. Characteristic cytological features such as small fascicles of spindle cells with blunt-ended nuclei, positivity for desmin and smooth muscle actin along with the radiological features are helpful in the correct diagnosis.

Transient splenial lesion: Further experience with two cases.

Transient splenial lesions (TSL) of the corpus callosum are uncommon radiologic findings that are seen in a number of clinical conditions with varied etiologies. They were first described a decade earlier in patients with epilepsy and hence were thought to be seizure or seizure therapy related. Subsequently, more cases were described by different observers in diseases with different etiologies, and the list is still increasing. Awareness of these lesions is necessary as they are an uncommon finding and have to be differentiated from other infective/noninfective causes. MRI is the imaging modality of choice as these lesions are not seen on routine noncontrast CT scan. The authors here describe two cases which showed TSL, with complete/partial resolution on follow-up scans. The authors also present a review of the literature.

Pancreaticopleural fistula: an unusual complication of pancreatitis diagnosed with magnetic resonance cholangiopancreatography.

CONTEXT: Pancreaticopleural fistula is a rare complication of pancreatitis. Pleural effusion resulting from a pancreaticopleural fistula is extremely rare and accounts for less than 1% of cases. Due to non-specific clinical presentations of a pancreaticopleural fistula, imaging plays an important role. Magnetic resonance cholangiopancreatography (MRCP) is very useful in depicting parenchymal and ductal structural changes along with direct visualization of a pancreaticopleural fistula. CASE REPORT: We present the case of a middle-aged male with moderate right pleural effusion who had a history of pancreatitis. MRCP showed chronic pancreatitis with a pancreaticopleural fistula. A brief review of the role of imaging in a pancreaticopleural fistula is discussed along with the case. CONCLUSION: MRCP is a useful modality for diagnosing a pancreaticopleural fistula.