Department Of Computational Sciences

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1-Hydroxypyrene-based micelle-forming sensors for the visual detection of RDX/TNG/PETN-based bomb plots in water
(Royal Society of Chemistry, 2018) Kovalev I.S.; Taniya O.S.; Kopchuk D.S.; Giri K.; Mukherjee A.; Santra S.; Majee A.; Rahman M.; Zyryanov G.V.; Bakulev V.A.; Chupakhin O.N.
The high-lying LUMO energy levels of common aliphatic nitro-explosives require special approaches for the proper synthetic design of fluorescence chemosensors that are capable to detect ultra-trace amounts of these explosives via photo-induced electron transfer (PET) fluorescence quenching. Herein, 1-hydroxypyrene has been used as a synthetic platform to prepare a number of water soluble micelle-forming fluorescent chemosensors possessing high-lying LUMO levels. Based on these sensors a cheap and highly efficient method has been described for the detection of low-volatile aliphatic nitro explosives, such as 1,3,5-trinitroperhydro-1,3,5-triazine (RDX), pentaerythritoltetranitrate (PETN), and high volatile taggants/propellants, such as 2,3-dimethyldinitrobutane (DMDNB) or trinitroglycerin (TNG) in aqueous solutions and in vapor phase. The applicability of the sensors for the detection of nitro-explosives was fully confirmed based on the fluorescence quenching titration experiments, with the corresponding Stern–Volmer constants as high as 6.0 × 105 M−1 and the limit of detection (LOD) as low as 12 ppb. The “sphere of action” quenching mechanism has been proposed. To support this, the DFT calculations of the possible molecular complexes between the sensors and nitro-analytes were performed along with the calculations of the quenching sphere radii for the Perrin's model.
3-Cyano-2-azaanthracene-based ‘‘push-pull” fluorophores: A one-step preparation from 5-cyano-1,2,4-triazines and 2,3-dehydronaphthalene, generated in situ
(Elsevier, 2016) Kopchuk, Dmitry S.; Chepchugov, Nikolay V.; Taniya, Olga S.; Khasanov, Albert F.; Giri,Kousik; Kovalev, Igor S.; Santara, Saugata; Zyryanov, Grigory V.; Majee, Adinath; Rusinov, Vladimir L.; Chupakhin, Oleg N.
A facile one-step approach towards 3-cyano-2-azaanthracenes via the [4+2] cycloaddition reaction between 5-cyano-1,2,4-triazines and 2,3-dehydronaphthalene, generated in situ from commercially available 3-amino-2-naphthoic acid, has been reported. The influence of the 1,2,4-triazine ring sub- stituents nature on the product yield has been studied. The observed experimental results were con- firmed by DFT calculations of the HOMO-LUMO energy levels of the both cycloaddends. The photophysical properties of the products have been investigated.
Advances in the computational methods to understand protein folding and stability
(Inderscience Publishers, 2022-11-09T00:00:00) Srikanth, Srimari; Srinivasan, Thamarai Selvi; Prabhu, Dhamodharan; Kadhirvel, Saraboji
Understanding the molecular basis of life is important for advances in fundamental and applied biological research. Numerous and complex biological activities occur simultaneously in all living cells in a controlled manner to execute an optimal equilibrium and function. Specifically, life depends on the regular functioning of the protein molecules, which depends upon the attainment of the correct three-dimensional structure and its stability. Therefore, deducing a fundamental understanding of how proteins fold and stabilise in the native states is of great intellectual and technological significance. Similar to all natural events, protein folding is a physicochemical process that is much more complex in-vivo, with the association of chaperones and/or other co-factors. Perturbations in protein�s stability results in misfolded proteins and their aggregated forms associated with protein misfolding disorders. Interestingly, researchers are involved in developing computational methods to predict the folded state of the protein and its stabilising mechanisms, which are essential in designing biotechnologically and medicinally important protein molecules. The present review aims to explore developments in the computational procedures which aid in understanding protein folding and stability and its applications. Copyright � 2021 Inderscience Enterprises Ltd.
Azaanthracenes via Inverse Electron-Demand Diels–Alder Reaction
(THIEME STUTTGART, 2016) Kopchuk, Dmitry S.; Chepchugov, N. V.; Taniya, Olga S.; Khasanov, A.F.; Giri,Kousik; Kovalev, Igor S.; Santra, S.; Zyryanov, Grigory V.; Majee, A.; Rusinov, V.L.; Chupakhin, O.N.
Significance: Azaanthracenes are important fluo- Comment: The benzyne derivative is generated in rophores that are used in a number of applications such as metal or pH sensors. In this report the authors describe a new synthesis of this type of structure via an inverse electron-demand aza- Diels–Alder reaction between a benzyne derivative and an electron-deficient triazine. situ from the diazotization of 2-amino-3-naphthoic acid. It was found that the cyano activating group at the 5-position of the triazine is crucial for the reaction to take place because it offers a smaller energy difference between the cycloaddition HOMO and LUMO.
A bioinformatics approach to solving the puzzle of autoimmune diseases
(Inderscience Publishers, 2022-12-13T00:00:00) Chatterjee, Durbadal; Parkash, Jyoti; Sharma, Arti
Autoimmune diseases are conditions in which the body attacks its own cells. In our study, we have taken eight autoimmune diseases, which are Addison�s disease, Graves� disease, Hashimoto�s thyroiditis, myasthenia gravis, psoriatic arthritis, pernicious anaemia, systematic lupus erythematosus and vasculitis. The pathways associated with these diseases are yet to be found. The underlying genes associated with each disease were predicted from the NCBI database. The mutual genes among these diseases have been identified. The digital gene expression of each gene has been anticipated. There are 668 genes associated with these eight diseases, and PTPN22 is identified as a mutual gene among seven out of the eight diseases. Most genes are involved in pathways related to the immune system, signal transduction and metabolism. All genes are expressed in the normal body condition, but in the case of disease, some genes are silenced, some show expression level changes in the diseased phenotypes and some genes have shown mutations but no expression change is reported, which leaves a question for further research. Copyright � 2022 Inderscience Enterprises Ltd.
Caesium carbonate promoted regioselective O-functionalization of 4,6-diphenylpyrimidin-2(1H)-ones under mild conditions and mechanistic insight
(Royal Society of Chemistry, 2023-06-05T00:00:00) Kumar, Vijay; Singh, Praval Pratap; Dwivedi, Ashish Ranjan; Kumar, Naveen; Rakesh kumar, None; Chandra Sahoo, Subash; Chakraborty, Sudip; Kumar, Vinod
A facile one-step catalyst free methodology has been developed for the regioselective functionalization of 4,6-diphenylpyrimidin-2(1H)-ones under mild conditions. Selectivity towards the O-regioisomer was achieved by using Cs2CO3 in DMF without use of any coupling reagents. A total of 14 regioselective O-alkylated 4,6-diphenylpyrimidines were synthesized in 81-91% yield. In the DFT studies it was observed that the transition state for the formation of the O-regioisomer is more favourable with Cs2CO3 as compared to K2CO3. Furthermore, this methodology was extended to increase the O/N ratio for the alkylation of 2-phenylquinazolin-4(3H)-one derivatives. � 2023 The Royal Society of Chemistry.
Comparative genomic and network analysis of nNOS by using different bioinformatics approaches
(Bentham Science Publishers, 2021-06-17T00:00:00) Arora, Nymphaea; Prashar, Vikash; Arora, Tania; Singh, Randeep; Mishra, Anshul; Godara, Priya; Banerjee, Arpita; Sharma, Arti; Parkash, Jyoti
Introduction: Nitric Oxide (NO) is a diatomic free radical gaseous molecule that is formed from L-arginine through NOS (Nitric oxide synthase) catalyzed reaction. NO controls vascular tone (hence blood pressure), insulin secretion, airway tone, and peristalsis, and is involved in angiogenesis (growth of new blood vessels) and development of the nervous system. In the CNS, NO is an important messenger molecule, which is involved in various major functions in the brain. NOS has been classified into three isoforms, including nNOS (neuronal NOS), eNOS (endothelial NOS) and iNOS (inducible NOS). NOS1 is localized on chromosome 12 consisting of 1434 amino acids and 161 KDa molecular weight. nNOS is involved in synaptic transmission, regulating the tone of smooth muscles and penile erection. We studied NOS1 gene and protein network analysis through in silico techniques as human nNOS sequence was fetched from GenBank and its homologous sequences were retrieved through BLAST search. Moreover, the results of this study exploit the role of NOS1 in various pathways, which provide ways to regulate it in various neurodegenerative diseases. Background: Previous research has revealed the role of Nitric Oxide (NO) formed from L-arginine through NOS (Nitric Oxide Synthase) as physiological inter/intra-cellular messenger in central as well as peripheral nervous systems. The diverse functions of NOS include insulin secretion, airway tone, vascular tone regulation, and in brain, it is involved in differentiation, development, synaptic plasticity and neurosecretion. Objective: The objective of this study is to unravel the role of neuronal Nitric Oxide Synthase (nNOS) in different pathways and its involvement as therapeutic target in various neurodegenerative disorders that can surely provide ways to regulate its activity in different aspects. Materials and Methods: In this study, we employed various bioinformatics tools and databases initiating the study by fetching the neuronal Nitric Oxide Synthase (nNOS) sequence (GenBank) to find its homologous sequences(BLAST) and then exploring its physical properties and post translational modifications, enhancing the research by network analysis (STRING), leading to its functional enrichment (Panther). Results: The results positively support the hypothesis of its role in various pathways related to neurodegeneration and its interacting partners are the probable therapeutic targets of various neurodegenerative diseases focusing on specifically multi-target analysis. Conclusion: This study considered evolutionary trend of physical, chemical and biological properties of NOS1 through different phyla. The neuronal Nitric Oxide Synthase (nNOS), being one of the three isoforms of NOS (Nitric Oxide Synthase), is found to be involved in more pathways than just forming Nitric Oxide. This research provides the base for further neurological research. � 2021 Bentham Science Publishers.
The Comparative Genomics and Network Analysis of eNOS by Using Different Bioinformatics Approaches
(Bentham Science Publishers, 2023-01-27T00:00:00) Banerjee, Arpita; Singh, Randeep; Arora, Nymphaea; Arora, Tania; Prashar, Vikash; Godara, Priya; Sharma, Arti; Changotra, Harish; Parkash, Jyoti
Background: Nitric oxide synthase (NOS) is an enzyme that catalyzes the synthesis of nitric oxide (NO) from L-arginine. It has three isoforms-(i) neuronal NOS (nNOS or NOS1), which participates in neural transmission; (ii) inducible NOS (iNOS or NOS2), which produces NO in macrophages; and (iii) endothelial NOS (eNOS or NOS3) that regulates blood pressure. The eNOS is mainly expressed in blood vessels and is a crucial regulator of endothelial homeostasis. Objective: The present study aimed to unravel the role of eNOS in different signaling pathways and its involvement as a therapeutic target in various neurodegenerative disorders. Methods: This study used various in silico methods for comprehensive genomic analysis of eNOS in 16 organisms from 7 different phyla. Prediction of conserved domains and evolutionary relationship for eNOS among 16 organisms was made. Various physical and chemical parameters, signal peptides, and transmembrane regions that helped understand its functional relevance were also studied. Results: Three transcription factor binding sites (TFBS), i.e., CP2, AR, and LDSPOLYA, were identified in human eNOS, while ATF1, T3R, and STAT1 were predicted in mouse eNOS. Transcription factors were identified for each regulatory region in human as well as mouse eNOS. eNOS protein was predicted to harbor 14 different post-translational modification (PTM) sites, most of which have phosphorylation (serine followed by threonine and tyrosine phosphorylation) followed by sumoylation and palmitoylation among all the organisms used in the current study. However, human eNOS has a relatively lower number of PTM sites for tyrosine phosphorylation. Conclusion: Structures of eNOS isoform, consistent with available biochemical and structural data, provide substantial insight into the NOS conformational changes, which give in-depth knowledge of the mechanism of eNOS, and will be helpful for better understanding the role of eNOS in pathophysiology. � 2023 Bentham Science Publishers.
Comparative Review Study of Security of ARAN and AODV Routing Protocols in MANETs
(eSAT Publishing House Private Limited, 2014) Goel, Ruby; Mittal, Meenakshi
Mobile Ad-hoc networks are proposed because there are some areas where it is not possible to set up a network having fixedinfrastructure, like in areas of emergency services, military operations, personal area networks, etc. Ad hoc network allowscommunication between wireless nodes with the help of their transmission ranges and routing protocols facilitate thiscommunication among the nodes. But on these routing protocols variety of attacks are possible like- Eavesdropping, IP-spoofing, Blackhole, Denial of service attack, etc. By attacking the routing protocol attackers can access network traffic, can drop it or canmodify it. To prevent these attacks many secure routing protocols like- SEAD, ARAN, SAODV, SRP, etc have been developed. Inthis paper security aspects of ARAN (Authenticated Routing for Adhoc Network routing protocol) has been analyzed with respectto a commonly used routing protocol AODV (Adhoc On-Demand Distance Vector) i.e. how much these two protocols are resistantto Blackhole and IP-Spoofing attack under GloMoSim-2.03 simulator.
Computational identification and experimental validation of anti-filarial lead molecules targeting metal binding/substrate channel residues of Cu/Zn SOD1 from Wuchereria bancrofti
(Taylor and Francis Ltd., 2022-10-28T00:00:00) Sureshan, Muthusamy; Prabhu, Dhamodharan; Kadhirvel, Saraboji
Lymphatic filariasis (LF) is a neglected mosquito-borne parasitic disease, widely caused by Wuchereria bancrofti (Wb) in tropical and sub-tropical countries. During a blood meal, the filarial nematodes are transmitted to humans by the infected mosquito. To counter attack the invaded nematodes, the human immune system produces reactive oxygen species. However, the anti-oxidant enzymes of nematodes counteract the host oxidative cytotoxicity. Cu/Zn Superoxide dismutase (SOD1), a member of antioxidant enzymes and are widely used by the nematodes to sustain the host oxidative stress across its lifecycle, hence targeting SOD1 to develop suitable drug molecules would help to overcome the problems related to efficacy and activity of drugs upon different stages of nematodes. In order to find the potent inhibitors, a three-dimensional structure of Cu/Zn WbSOD1 was modelled and the structural stability was analysed through simulation studies. The structure-guided virtual screening approach has been used to identify lead molecules from the ChemBridge based on the docking score, ADMET properties and protein�ligand complex stability analysis. The identified compounds were observed to interact with the copper, metal binding residues (His48, His63, His80 and His120) and catalytically important residue Arg146, which play a crucial role in the disproportionation of incoming superoxide radicals of Cu/Zn WbSOD1. Further, in�vitro validation of the selected leads in the filarial worm Setaria digitata exhibited higher inhibition and better IC50 compared to the standard drug ivermectin. Thus, the identified leads could potentially inhibit enzyme activity, which could subsequently act as drug candidates to control LF. Communicated by Ramaswamy H. Sarma. � 2022 Informa UK Limited, trading as Taylor & Francis Group.
Confined Water: Structure, Dynamics, and Thermodynamics
(American Chemical Society, 2017) Chakraborty, S.; Kumar, H.; Dasgupta, C.; Maiti, P.K.
ConspectusUnderstanding the properties of strongly confined water is important for a variety of applications such as fast flow and desalination devices, voltage generation, flow sensing, and nanofluidics. Confined water also plays an important role in many biological processes such as flow through ion channels. Water in the bulk exhibits many unusual properties that arise primarily from the presence of a network of hydrogen bonds. Strong confinement in structures such as carbon nanotubes (CNTs) substantially modifies the structural, thermodynamic, and dynamic (both translational and orientational) properties of water by changing the structure of the hydrogen bond network. In this Account, we provide an overview of the behavior of water molecules confined inside CNTs and slit pores between graphene and graphene oxide (GO) sheets.Water molecules confined in narrow CNTs are arranged in a single file and exhibit solidlike ordering at room temperature due to strong hydrogen bonding between nearest-neighbor molecules. Although molecules constrained to move along a line are expected to exhibit single-file diffusion in contrast to normal Fickian diffusion, we show, from a combination of molecular dynamics simulations and analytic calculations, that water molecules confined in short and narrow CNTs with open ends exhibit Fickian diffusion because of their collective motion as a single unit due to strong hydrogen bonding.Confinement leads to strong anisotropy in the orientational relaxation of water molecules. The time scale of relaxation of the dipolar correlations of water molecules arranged in a single file becomes ultraslow, of the order of several nanoseconds, compared with the value of 2.5 ps for bulk water. In contrast, the relaxation of the vector that joins the two hydrogens in a water molecule is much faster, with a time scale of about 150 fs, which is about 10 times shorter than the corresponding time scale for bulk water. This is a rare example of confinement leading to a speedup of orientational dynamics. The orientational relaxation of confined water molecules proceeds by angular jumps between two locally stable states, making the relaxation qualitatively different from that expected in the diffusive limit.The spontaneous entry of water inside the hydrophobic cavity of CNTs is primarily driven by an increase in the rotational entropy of water molecules inside the cavity, arising from a reduction in the average number of hydrogen bonds attached to a water molecule. From simulations using a variety of water models, we demonstrate that the relatively simple SPC/E water model yields results in close agreement with those obtained from polarizable water models.Finally, we provide an account of the structure and thermodynamics of water confined in the slit pore between two GO sheets with both oxidized and reduced parts. We show that the potential of mean force for the oxidized part of GO sheets in the presence of water exhibits two local minima, one corresponding to a dry cavity and the other corresponding to a fully hydrated cavity. The coexistence of these two regimes provides permeation pathways for water in GO membranes. ? 2017 American Chemical Society.
Could mycobacterial MelF protein (Rv1936) be used as a potential drug target?
(Future Medicine Ltd., 2018) Mehta P.K.; Dharra R.; Kulharia, Mahesh
CuO Nanoparticles as a Simple and Efficient Green Catalyst for the Aziridine Ring-Opening: Examination of a Broad Range of Nucleophiles
(Wiley-Blackwell, 2020) Chatterjee, R; Santra, S; Chakraborty, Ghosal N; Giri, K; Zyryanov, G.V; Majee, A.
It has been observed that CuO nanoparticles act as effective and reusable catalyst for the ring-opening reaction of aziridines with a wide range of nucleophiles such as alcohols, thiols, and indoles. The catalytic activity has been tested in large scale reactions. The methodology is applicable in very low catalyst loading. The reaction proceeds under solvent-free conditions. The catalyst has been used for six consecutive cycles with comparable efficiency. The present methodology could be considered as environmentally benign as indicated by the calculation of E-factors which are very low in the range of 0.37-1.31. - 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Designing specific inhibitors against dihydrofolate reductase of W. bancrofti towards drug discovery for lymphatic filariasis
(Springer, 2022-03-15T00:00:00) Sureshan, Muthusamy; Rajamanikandan, Sundarraj; Srimari, Srikanth; Prabhu, Dhamodharan; Jeyakanthan, Jeyaraman; Saraboji, Kadhirvel
Lymphatic filariasis (LF) is one among the leading neglected diseases caused by mosquitoe-borne parasite Wuchereria bancrofti to humans. Though drugs are available for the treatment of LF, all of which are not effective in all stages and moreover majority of these drugs have been reported with resistance. There is a need for effective new drugs which affect the parasite irrespective of its lifecycle and counter the drug resistance mechanisms. In the present study, we have explored the key enzyme dihydrofolate reductase (DHFR) as the potential target for developing drugs against LF. We have modelled dihydrofolate reductase structure and analysed its stability through the 200�ns simulation studies. Computer-assisted screening method found five non-toxic potent hit molecules with a docking score of ? 13.86 to ? 13.54�kcal/mol. Interestingly, we observed that the identified hit molecules are more specific to W. bancrofti DHFR than human DHFR due to electrostatic charge variations in the binding cavity. Higher specificity could increase the therapeutic efficacy and also minimize cross-reactivity with human targets. We have also found that the identified hit molecules have better glide score and energy than the reported DHFR inhibitors of W. bancrofti. Better score and energy values depict that the identified hit molecules could inhibit the DHFR activity efficiently. The DFT analysis predicted the regions in the hit molecules with higher probability of chemical reactivity and also potential sites to enhance the binding efficiency. Our findings provide new scaffolds for the development of DHFR inhibitors, which can be efficiently formulated to treat LF. � 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Development and validation of a robust QSAR model for benzothiazole hydrazone derivatives as Bcl-XL inhibitors
(Bentham Science Publishers B.V., 2018) Gupta P.; Gutcaits A.
Background: B-cell Lymphoma Extra Large (Bcl-XL) belongs to B-cell Lymphoma two (Bcl-2) family. Due to its over-expression and anti-apoptotic role in many cancers, it has been proven to be a more biologically relevant therapeutic target in anti-cancer therapy. In this study, a Quantitative Structure Activity Relationship (QSAR) modeling was performed to establish the link between structural properties and inhibitory potency of benzothiazole hydrazone derivatives against Bcl-XL. Methods: The 53 benzothiazole hydrazone derivatives have been used for model development using genetic algorithm and multiple linear regression methods. The data set is divided into training and test set using Kennard-Stone based algorithm. The best QSAR model has been selected with statistically significant r2 = 0.931, F-test =55.488 RMSE = 0.441 and Q2 0.900. Results: The model has been tested successfully for external validation (r2 pred = 0.752), as well as different criteria for acceptable model predictability. Furthermore, analysis of the applicability domain has been carried out to evaluate the prediction reliability of external set molecules. The developed QSAR model has revealed that nThiazoles, nROH, EEig13d, WA, BEHv6, HATS6m, RDF035u and IC4 descriptors are important physico-chemical properties for determining the inhibitory activity of these molecules. Conclusion: The developed QSAR model is stable for this chemical series, indicating that test set molecules represent the training dataset. The model is statistically reliable with good predictability. The obtained descriptors reflect important structural features required for activity against Bcl-XL. These properties are designated by topology, shape, size, geometry, substitution information of the molecules (nThiazoles and nROH) and electronic properties. In a nutshell, these characteristics can be successfully utilized for designing and screening of novel inhibitors.
Discovery of plant-based phytochemical�as effective antivirals that target the non-structural protein C of the Nipah virus through computational methods
(Taylor and Francis Ltd., 2023-05-24T00:00:00) Sureshan, Muthusamy; Prabhu, Dhamodharan; Joshua, Sharon Nissi; Sasikumar, Shruti Vardhini; Rajamanikandan, Sundarraj; Govindhapriya, Muthukumar; Umadevi, Venkatachalam; Kadhirvel, Saraboji
Nipah Virus (NiV) belongs to the Paramyxoviridae family and was first identified during an outbreak in Malaysia. Some initial symptoms include mild fever, headache and sore throat, which could escalate to respiratory illness and brain inflammation. The mortality rate of NiV infection can range from 40% to 75%, which is quite high. This is mainly due to the lack of efficient drugs and vaccines. In most instances, NiV is transmitted from animals to humans. Non-Structural Proteins (C, V and W) of the Nipah virus impede the host immune response by obstructive the JAK/STAT pathway. However, Non-Structural Proteins�C (NSP-C) plays a vital role in NiV pathogenesis, which includes IFN antagonist activity and viral RNA production. In the present study, the full-length structure of NiV-NSP-C was predicted using computational modelling, and the stability of the structure was analysed using 200 ns molecular dynamic (MD) simulation. Further, the structure-based virtual screening identified five potent phytochemicals (PubChem CID: 9896047, 5885, 117678, 14887603 and 5461026) with better binding affinity against NiV-NSP-C. DFT studies clearly showed that the phytochemicals had higher chemical reactivity, and the complex MD simulation depicted that the identified inhibitors exhibited stable binding with NiV-NSP-C. Furthermore, experimental validation of these identified phytochemicals would likely control the infection of NiV. Communicated by Ramaswamy H. Sarma. � 2023 Informa UK Limited, trading as Taylor & Francis Group.
Discovery of potent inhibitors targeting Glutathione S-transferase of Wuchereria bancrofti: a step toward the development of effective anti-filariasis drugs
(Institute for Ionics, 2023-02-16T00:00:00) Sureshan, Muthusamy; Prabhu, Dhamodharan; Rajamanikandan, Sundarraj; Saraboji, Kadhirvel
Lymphatic filariasis (LF) is one of the major health problems for the human kind in developing countries including India. LF is caused by three major nematodes namely Wuchereria bancrofti, Brugia malayi, and Brugia timori. The recent statistics of World Health Organization (WHO) showed that 51 million people were affected and 863 million people from 47 countries around worldwide remain threatened by LF. Among them, 90% of the filarial infection was caused by the nematode W. bancrofti. Approved drugs were available for the treatment of LF but many of them developed drug resistance and no longer effective in all stages of the infection. In the current research work, we explored the Glutathione S-transferase (GST) of W. bancrofti, the key enzyme responsible for detoxification that catalyzes the conjugation of reduced GSH (glutathione) to xenobiotic compounds. Initially, we analyzed the stability of the WbGST through 200 ns MD simulation and further structure-based virtual screening approach was applied by targeting the substrate binding site to identify the potential leads from small molecule collection. The in silico ADMET profiles for the top-ranked hits were predicted and the predicted non-toxic lead molecules showed the highest docking score in the range of ?�12.72 kcal/mol to ?�11.97 kcal/mol. The cross docking of the identified hits with human GST revealed the potential binding specificity of the hits toward WbGST. Through WbGST�lead complex simulation, the lead molecules were observed to be stable and also intactly bound within the binding site of WbGST. Based on the computational results, the five predicted non-toxic molecules were selected for the in vitro assay. The molecules showed significant percentage of inhibition against the filarial worm Setaria digitata which is the commonly used model organism to evaluate the filarial activity. In addition, the molecules also showed better IC50 than the standard drug ivermectin. The identified lead molecules will lay a significant insight for the development of new drugs with higher specificity and lesser toxicity to control and treat filarial infections. Graphical abstract: [Figure not available: see fulltext.] � 2023, The Author(s), under exclusive licence to Springer Nature Switzerland AG.
Disruptive influence of the host cage C60 on the guest He�H+ bond and bonding in H3+
(Elsevier B.V., 2021-07-13T00:00:00) Giri, Kousik; Mishra, Brijesh K.; Sathyamurthy, Narayanasami
Although a helium atom prefers to stay at the centre of a fullerene (C60) cage and a proton binds with one of the carbon atoms from inside, DFT(MN15)/cc-pVTZ and DLPNO-MP2/def2-TZVP calculations show that the helium atom and the proton in HeH+ prefer to stay away from the centre of the cage, weakening the He�H+ covalent bond considerably. Both the helium atom and the proton exhibit noncovalent interactions with the carbon atoms of two pentagons at the opposite ends of the fullerene cage. Our calculations also show that a linear arrangement of H3+ (inside C60), pointing towards the centres of two pentagons opposite to each other, with the proton breaking away from H2, is energetically more favored over the equilateral triangle geometry of free H3+. � 2021 Indian Chemical Society
Dysregulated miRNAs in Progression and Pathogenesis of Alzheimer�s Disease
(Springer, 2022-07-22T00:00:00) Arora, Tania; Prashar, Vikash; Singh, Randeep; Barwal, Tushar Singh; Changotra, Harish; Sharma, Arti; Parkash, Jyoti
Alzheimer�s disease (AD) is a progressive degeneration of neurons due to the accumulation of amyloid-? peptide (A?) and hyper-phosphorylation of tau protein in the neuronal milieu leading to increased oxidative stress and apoptosis. Numerous factors contribute towards the progression of AD, including miRNA, which are 22�24 nucleotides long sequence which acts as critical regulators of cellular processes by binding to 3? UTR of mRNA, regulating its expression post-transcriptionally. This review aims to determine the miRNA with the most significant dysregulation in the brain and cerebrospinal fluid (CSF) of human patients. A systemized inclusion/exclusion criterion has been utilized based on selected keywords followed by screening of those articles to conclude a list of 8 highly dysregulated miRNAs based on the fold change of AD vs control patients, which could be used in clinical testing as these miRNAs play central role in the pathophysiology of AD. Furthermore, a network study of highly dysregulated miRNA estimated the association of these miRNA in the mediation of A? generation and aggregation, inhibition of autophagy, reduction of A? clearance, microglial and astrocytic activation, neuro-inflammation, tau hyper-phosphorylation, and synaptic loss. � 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Effect of arsenate substitution on phosphate repository of cell: A computational study
(Royal Society Publishing, 2018) Singh A.; Giri K.
The structural analogy with phosphate derives arsenate into various metabolic processes associated with phosphate inside the organisms. But it is difficult to evaluate the effect of arsenate substitution on the stability of individual biological phosphate species, which span from a simpler monoester form like pyrophosphate to a more complex phosphodiester variant like DNA. In this study, we have classified the physiological phosphate esters into three different classes on the basis of their structural differences. This classification has helped us to present a concise theoretical study on the kinetic stability of phosphate analogue species of arsenate against hydrolysis. All the calculations have been carried out using QM/MM methods of our Own N-layer Integrated molecular Orbital molecular Mechanics (ONIOM). For quantum mechanical region, we have used M06-2X density functional with 6-31+G(2d,2p) basis set and for molecular mechanics we have used the AMBER force field. The calculated rate constants for hydrolysis show that none of the phosphate analogue species of arsenate has a reasonable stability against hydrolysis.

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