| 1. |
- Gahlawat, Anuj, et al.
(author)
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Structure-Based Virtual Screening to Discover Potential Lead Molecules for the SARS-CoV-2 Main Protease.
- 2020
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In: Journal of Chemical Information and Modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 60:12, s. 5781-5793
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Journal article (peer-reviewed)abstract
- The COVID-19 disease is caused by a new strain of the coronavirus family (SARS-CoV-2), and it has affected at present millions of people all over the world. The indispensable role of the main protease (Mpro) in viral replication and gene expression makes this enzyme an attractive drug target. Therefore, inhibition of SARS-CoV-2 Mpro as a proposition to halt virus ingression is being pursued by scientists globally. Here we carried out a study with two objectives: the first being to perform comparative protein sequence and 3D structural analysis to understand the effect of 12 point mutations on the active site. Among these, two mutations, viz., Ser46 and Phe134, were found to cause a significant change at the active sites of SARS-CoV-2. The Ser46 mutation present at the entrance of the S5 subpocket of SARS-CoV-2 increases the contribution of other two hydrophilic residues, while the Phe134 mutation, present in the catalytic cysteine loop, can cause an increase in catalytic efficiency of Mpro by facilitating fast proton transfer from the Cys145 to His41 residue. It was observed that active site remained conserved among Mpro of both SARS-CoVs, except at the entrance of the S5 subpocket, suggesting sustenance of substrate specificity. The second objective was to screen the inhibitory effects of three different data sets (natural products, coronaviruses main protease inhibitors, and FDA-approved drugs) using a structure-based virtual screening approach. A total of 73 hits had a combo score >2.0. Eight different structural scaffold classes were identified, such as one/two tetrahydropyran ring(s), dipeptide/tripeptide/oligopeptide, large (approximately 20 atoms) cyclic peptide, and miscellaneous. The screened hits showed key interactions with subpockets of the active site. Further, molecular dynamics studies of selected screened compounds confirmed their perfect fitting into the subpockets of the active site. This study suggests promising structures that can fit into the SARS-CoV-2 Mpro active site and also offers direction for further lead optimization and rational drug design.
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| 2. |
- Kumar, Vikas, et al.
(author)
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Computational insights into allosteric inhibition of focal adhesion kinase: A combined pharmacophore modeling and molecular dynamics approach
- 2024
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In: JOURNAL OF MOLECULAR GRAPHICS & MODELLING. - 1093-3263 .- 1873-4243. ; 130
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Journal article (peer-reviewed)abstract
- Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that modulates integrin and growth factor signaling pathways and is implicated in cancer cell migration, proliferation, and survival. Over the past decade various, FAK kinase, FERM, and FAT domain inhibitors have been reported and a few kinase domain inhibitors are under clinical consideration. However, few of them were identified as multikinase inhibitors. In kinase drug design selectivity is always a point of concern, to improve selectivity allosteric inhibitor development is the best choice. The current research utilized a pharmacophore modeling (PM) approach to identify novel allosteric inhibitors of FAK. The all-available allosteric inhibitor bound 3D structures with PDB ids 4EBV, 4EBW, and 4I4F were utilized for the pharmacophore modeling. The validated PM models were utilized to map a database of 770,550 compounds prepared from ZINC, EXIMED, SPECS, ASINEX, and InterBioScreen, aiming to identify potential allosteric inhibitors. The obtained compounds from screening step were forwarded to molecular docking (MD) for the prediction of binding orientation inside the allosteric site and the results were evaluated with the known FAK allosteric inhibitor (REF). Finally, 14 FAK-inhibitor complexes were selected from the docking study and were studied under molecular dynamics simulations (MDS) for 500 ns. The complexes were ranked according to binding free energy (BFE) and those demonstrated higher affinity for allosteric site of FAK than REF inhibitors were selected. The selected complexes were further analyzed for intermolecular interactions and finally, three potential allosteric inhibitor candidates for the inhibition of FAK protein were identified. We believe that identified scaffolds may help in drug development against FAK as an anticancer agent.
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| 3. |
- Verma, Suresh K., et al.
(author)
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The posterity of Zebrafish in paradigm of in vivo molecular toxicological profiling
- 2024
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In: Biomedicine and Pharmacotherapy. - : Elsevier. - 0753-3322 .- 1950-6007. ; 171
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Research review (peer-reviewed)abstract
- The aggrandised advancement in utility of advanced day-to-day materials and nanomaterials has raised serious concern on their biocompatibility with human and other biotic members. In last few decades, understanding of toxicity of these materials has been given the centre stage of research using many in vitro and in vivo models. Zebrafish (Danio rerio), a freshwater fish and a member of the minnow family has garnered much attention due to its distinct features, which make it an important and frequently used animal model in various fields of embryology and toxicological studies. Given that fertilization and development of zebrafish eggs take place externally, they serve as an excellent model organism for studying early developmental stages. Moreover, zebrafish possess a comparable genetic composition to humans and share almost 70% of their genes with mammals. This particular model organism has become increasingly popular, especially for developmental research. Moreover, it serves as a link between in vitro studies and in vivo analysis in mammals. It is an appealing choice for vertebrate research, when employing high-throughput methods, due to their small size, swift development, and relatively affordable laboratory setup. This small vertebrate has enhanced comprehension of pathobiology and drug toxicity. This review emphasizes on the recent developments in toxicity screening and assays, and the new insights gained about the toxicity of drugs through these assays. Specifically, the cardio, neural, and, hepatic toxicology studies inferred by applications of nanoparticles have been highlighted.
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| 6. |
- Bhattacharjee, Rahul, et al.
(author)
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Synergy of nanocarriers with CRISPR-Cas9 in an emerging technology platform for biomedical appliances : Current insights and perspectives
- 2022
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In: Materials & design. - : Elsevier. - 0264-1275 .- 1873-4197. ; 224
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Journal article (peer-reviewed)abstract
- Genetic editing technologies have emerged as a potential therapeutic tool in various biomedical fields owing to their applications against cancer, neurological diseases, diabetes, autoimmune disorder, muscu-lar dystrophy, bacterial infections (AMR), and cardiovascular diseases. CRISPR is one such valuable genetic editing tool with extensive therapeutic appliances but with a major challenge in terms of deliv-ery. Herein, we have strived to exploit a synergy of nanocarriers and CRISPR against the aforementioned diseases for their medical applications and explicated their clinical significance including the enhanced delivery via endosomal escape and environmental factors such as light, pH, and stimuli. In addition to highlighting the delivery strategies of nano-carriers for CRISPR and their characterization, we have expounded on the reliant factor of the CRISPR-Cas Complex.
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| 7. |
- Dhumal, Tushar Tukaram, et al.
(author)
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Molecular explorations of the Leishmania donovani 6-phosphogluconolactonase enzyme, a key player in the pentose phosphate pathway
- 2022
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In: Biochimie. - : Elsevier BV. - 0300-9084 .- 1638-6183. ; 202, s. 212-225
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Journal article (peer-reviewed)abstract
- The enzymes of the pentose phosphate pathway are vital to survival in kinetoplastids. The second step of the pentose phosphate pathway involves hydrolytic cleavage of 6-phosphogluconolactone to 6- phosphogluconic acid by 6-phosphogluconolactonase (6PGL). In the present study, Leishmania dono-vani 6PGL (Ld6PGL) was cloned and overexpressed in bacterial expression system. Comparative sequence analysis revealed the conserved sequence motifs, functionally and structurally important residues in 6PGL family. In silico amino acid substitution study and interacting partners of 6PGL were predicted. The Ld6PGL enzyme was found to be active in the assay and in the parasites. Specificity was confirmed by Western blot analysis. The similar to 30 kDa protein was found to be a dimer in MALDI, glutaraldehyde cross-linking and size exclusion chromatography studies. Kinetic analysis and structural stability studies of Ld6PGL were performed with denaturants and at varied temperature. Computational 3D Structural modelling of Ld6PGL elucidates that it has a similar a/b hydrolase fold structural topology as in other members of 6PGL family. The three loops are found in extended form when the structure is compared with the human 6PGL (Hs6PGL). Further, enzyme substrate binding mode and its mechanism were investigated using the molecular docking and molecular simulation studies. Interesting dynamics action of substrate 6-phosphogluconolactone was observed into active site during MD simulation. Interesting differences were observed between host and parasite enzyme which pointed towards its potential to be explored as an antileishmanial drug target. This study forms the basis for further analysis of the role of Ld6PGL in combating oxidative stress in Leishmania.
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| 8. |
- Singh, Rajesh, et al.
(author)
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Removal of sulphate, COD and Cr(VI) in simulated and real wastewater by sulphate reducing bacteria enrichment in small bioreactor and FTIR study
- 2011
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In: Bioresource Technology. - : Elsevier BV. - 0960-8524 .- 1873-2976. ; 102:2, s. 677-682
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Journal article (peer-reviewed)abstract
- The present study was conducted to investigate the chromium(VI), COD and sulphate removal efficiency from aqueous solution and treatment of real effluent (CETP) in a small scale bioreactor using sulphate reducing bacteria consortium. Effect of different hydraulic retention times (HRTs), initial metal concentrations, various carbon sources and temperatures were studied on removal of chromium(VI), COD and sulphate. Maximum chromium(VI) and sulphate removal was found to be 96.0% and 82.0%, respectively, at initial concentration of 50 mg l(-1) using lactate as carbon source. However, highest COD removal was 36.2% in medium containing fructose as the carbon source and electron donor. NADH dependent chromate reductase activity was not observed which indicated the anaerobic consortium. Initially consortium medium with a strong negative oxidation reduction potential indicated the reducing activity. The FTIR spectrum of the sulphate reducing bacteria consortium clearly shows the existence of the sulphate ions and signifies that sulfate reducing bacteria have used sulfate during the growth phase.
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| 9. |
- Thamke, Viresh, 1985-, et al.
(author)
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Current toxicological insights of ionic liquids on various environmental living forms
- 2022
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In: Journal of Environmental Chemical Engineering. - : Elsevier. - 2213-3437. ; 10:2
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Journal article (peer-reviewed)abstract
- Ionic liquids (ILs), are organic salts and have been referred to as greener solvents, oftentimes also termed designer solvents. They are separated into classes namely room temperature ILs (RTILs), task-specific ILs (TSILs), polyionic liquids (PLILs), and supported ILs, among others. ILs are used as solvents because of their low vapour pressure at room temperature as well as thermal stability. Because of their widespread applications in diverse fields, they may contribute to contaminating the land and aquatic environment as the majority of them are chemically stable. Although many researchers have labelled the ILs as green in nature there is an enormous possibility for their release into the environment in many ways. Although the variety of ILs and their synthesis are continuously increasing however scant attention has been paid to their remediation strategies; toxicological information generated in the last decade does provide a report on the impact of ILs on lower organisms and plants. Therefore, to enhance the toxicological understanding of ILs, it is a prerequisite to assemble their recent toxicological information on various living forms. This knowledge certainly will offer new clues about their interaction at the physiological and molecular scale of an organism and thus contribute to the fulfilling gap in our toxicological understanding. Hence, this review article highlights the recent toxicological impact of newly synthesized ILs on microbes, vertebrates, invertebrates, animal cells, and plants where the summarised toxicological facts have expounded the effect of ILs in dose dependent manner associated with their structure. Similarly, the impact of various ILs at the cellular level of the organism is discussed. This review also sums up the current development of computational modelling for evaluation of toxicity testing that may minimize the animal experimental dependency thus providing a future guideline in designing the greener ILs.
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