Pankaj Chetia

Atherogenic effect of Arecoline: A computational study

There are over 600 million people worldwide covering Asian and Oceanic countries including India have the habit of chewing areca nut as masticator in different forms. Arecoline (C8H13NO2) has been reported as one of the abundant constituents of areca nut. A good number of scientific publications have made Arecoline responsible for oral cancer. Based on observation from clinical situation in North East India, one of the most betel quid chewing region of the country, we suspected a link between consumption of areca nut and Cerebro Vascular Disease like stroke. Therefore, we considered Low Density Lipoprotein (LDL) receptor as target and Arecoline as ligand and studied ligand –target interaction using computational tools. Also we considered High Density Lipoprotein (HDL) receptor as another target to see if Arecoline has any binding potential with it over and above LDL receptor. Docking result indicated that Arecoline and Cholesterol both, have affinity towards extracellular domain of Human LDL receptor but affinity of Arecoline is much higher (-12.3560.) than that of Cholesterol(-0.1810). Docking of Arecoline and 1, 2-Hexyl-1- cyclopentanone thiosemicarbazone (thiosemicarbazone) with Bovine HDL receptor showed that Arecoline also has the potential (Score, -6.2690Kcal/Mol) to block HDL receptor though its potential is less than that (score, -10.0509 Kcal/Mol) of control (thiosemicarbazone). We, therefore, suggest that by inhibiting endocytosis of LDL cholesterol because of blocking LDL receptor function and also by preventing LDL cholesterol uptake by liver from blood because of interference with HDL receptor, Arecoline may contribute to atherosclerosis. The study therefore, indicates a positive correlation between chewing of betel quid and Cerebro Vascular Disease.

Screening of Natural Products and Derivatives for the Identification of RND Efflux Pump Inhibitors

AIM AND OBJECTIVE Overexpression of efflux pumps belonging to the Resistance Nodulation cell Division (RND) family is the most important intrinsic resistance mechanism of Pseudomonas aeruginosa. Hence, it is imperative to identify suitable efflux pump inhibitors (EPI) that can lead to increased intracellular concentration of antibiotics by blocking the pump. This study was undertaken to identify a putative plant based efflux pump inhibitor for RND efflux pump of P. aeruginosa. MATERIAL AND METHOD Using molecular docking approach, 328 secondary plant metabolites have been screened for their inhibitory activity against cytoplasmic exporter protein MexB of MexAB-OprM efflux pump of P. aeruginosa. After the initial in silico screening, the shortlisted compounds were subjected to in vitro test for efflux pump inhibitory activity using double disc synergy test. A combinatorial library of 1000 molecules was generated from active p-coumaric acid and docked with MexB protein to find a suitable EPI with better binding efficacy compared to the p-coumaric acid. RESULTS Preliminary screening resulted in five plant-based natural products with significant docking score and were subsequently subjected to double disc synergy test. p-Coumaric acid , amongst the five, was found to potentiate activity of ciprofloxacin in MexAB-OprM overexpressing P. aeruginosa strain. Library compound 482, i.e 4-(4-((Z)-2-carboxy-2-((Z)-2,3-dihydrobenzo[e][1,4]diazepin-1-yl)-1-(4- hydroxyphenyl)vinylamino) phenylsulfonamido)-2-hydroxybenzoic acid, a derivative of p-coumaric acid exhibited the highest docking score of -42.1030 Kcal/mol, which was much higher than parent compound (-17.9403 Kcal/mol) and also known EPI, MC-207,110 (-28.0960 Kcal/mol). CONCLUSION p-Coumaric acid and its derivative, 4-(4-((Z)-2-carboxy-2-((Z)-2,3-dihydrobenzo[e][1,4] diazepin-1-yl)-1-(4-hydroxyphenyl)vinylamino)phenylsulfonamido)-2-hydroxybenzoic acid may be used as potential lead molecules for effective RND efflux pump inhibition in P. aeruginosa.

Computational validation of 3-ammonio-3-(4-oxido- 1H-imidazol-1-ium-5-yl) propane-1, 1-bis (olate) as a potent anti-tubercular drug against mt-MetAP.

The advent of Multi Drug Resistant (MDR) strain of Mycobacterium tuberculosis (TB) necessitated search for new drug targets for the bacterium. It is reported that 3.3% of all new tuberculosis cases had multidrug resistance (MDR-TB) in 2009 and each year, about 0.44 million MDR-TB cases are estimated to emerge and 0.15 million people with MDR-TB die. Keeping such an alarming situation under consideration we wanted to design suitable anti tubercular molecules for new target using computational tools. In the work Methionine aminopeptidase (MetAP) of Mycobacterium tuberculosis was considered as target and three non-toxic phenolic=ketonic compounds were considered as ligands. Docking was done with Flex X and AutoDock 4.2 separately. Ten proven inhibitors of MetAP were collected from literature with their IC50 and were correlated using EasyQSAR to generate QSAR model. Activity of ligands in question was predicted from QSAR. Pharmacophore for each docking was generated using Ligandscout 3.0. Toxicity of the ligands in question was predicted on Mobyle@rpbs portal and Actelion property explorer. Molecular docking with target showed that of all three ligands, 3-ammonio-3-(4-oxido-1H-imidazol-1-ium-5-yl) propane-1, 1-bis (olate) has highest affinity (- 37.5096) and lowest IC50 (4.46 µM). We therefore, propose that -3-ammonio-3-(4-oxido-1H-imidazol-1-ium-5-yl) propane-1,1- bis(olate) as a potent MetAP inhibitor may be a new anti-tubercular drug particularly in the context of Multi Drug Resistant Tuberculosis (MDR-TB).

An In Silico Appraisal of Azoic and Disulphide Derivatives for Anticancer Activity Against HPV E6 Oncoprotein to Medicate Cervical Cancer

Cervical cancer is the second largest form of cancer to infest the leading cause of death in women worldwide. There are many causes of cancer but viruses are the most common among them. Human papillomaviruses (HPVs) are found to be the causative organism in almost 99.7% of the cases. HPV16 is the most frequent HPV type in malignant neoplastic growth in about 60% of cervical carcinoma cases. There is limited success achieved in surgical removal or by immune modulation and more effective therapies are under investigation. Observing the mortality rate we theorize a need for alternative treatment approaches and propose a blueprint of compounds with desirable properties that may lead to the development of drugs to treat HPV-associated neoplasias. E6 oncoprotein of HPV16 has a potential zinc finger domain critical for binding to E6AP, causing p53 degradation and malignancy. Some azoics and disulfides were selected depending on their affinity towards E6 zinc finger and thereby preventing E6-E6AP complex formation. Combinatorial nontoxic derivatives of these azoics and disulfides were docked and validated against the oncoprotein to inhibit E6-E6AP interaction. Among these, two compounds (E)-N-(2-amino-2-oxoethyl)-N-(4-chlorophenyl) diazene-1,2-dicarboxamide and (E)-N-(2- amino-2-methylpropyl)-N-(thiophen-2-yl)diazene-1,2-dicarboxamide showed binding affinity of -23.70, -19.53 and -5.49, -4.65 Kcal/mol respectively in FlexX and Autodock4.2. These compounds are found more effective than those of the approved E6-E6AP binding inhibitors. Pharmacophores of these compounds were generated to confirm it with pharm mapping mechanism. The study may confer the way of design of new mechanism and new compounds to treat cervical cancer.

Emergence of antibiotic resistant Shigella species: A matter of concern

A major threat to the world is the emergence of antibiotic resistant bacteria, which has rendered previously susceptible drugs useless and increased the rate of therapeutic failures. Shigella species, which are the causative organism of Shigellosis, were earlier susceptible to ampicillin, chloramphenicol, co-trimoxazole and nalidixic acid but now they have developed resistance against fluoroquinolones, cephalosporins and azithromycin. Many shigellosis outbreaks have been reported by resistant strains of Shigella species. This review attempts to provide a brief overview about the scenario of shigellosis and the emergence as well as ubiquitous nature of multidrug resistant (MDR) Shigella species.

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.