Department Of Biochemistry And Microbial Sciences
Permanent URI for this communityhttps://kr.cup.edu.in/handle/32116/23
Browse
6 results
Search Results
Item Specific Genetic Polymorphisms Contributing in Differential Binding of Gliadin Peptides to HLA-DQ and TCR to Elicit Immunogenicity in Celiac Disease(Springer, 2023-04-27T00:00:00) Banerjee, Pratibha; Chaudhary, Ramprasad; Singh, Atul Kumar; Parulekar, Pratima; Kumar, Shashank; Senapati, SabyasachiImmunogenicity of gliadin peptides in celiac disease (CD)�is majorly determined by the pattern of molecular interactions with HLA-DQ and T-cell receptors (TCR). Investigation of the interactions between immune-dominant gliadin peptides, DQ protein, and TCR are warranted to unravel the basis of immunogenicity and variability contributed by the genetic polymorphisms. Homology modeling of HLA and TCR done using Swiss Model and iTASSER, respectively. Molecular interactions of eight common deamidated immune-dominant gliadin with HLA-DQ allotypes and specific TCR gene pairs were evaluated. Docking of the three structures was performed with ClusPro2.0 and ProDiGY was used to predict binding energies. Effects of known allelic polymorphisms and reported susceptibility SNPs were predicted on protein�protein interactions. CD susceptible allele, HLA-DQ2.5 was shown to have considerable binding affinity to 33-mer gliadin (?G = ?�13.9; Kd = 1.5E�?�10) in the presence of TRAV26/TRBV7. Higher binding affinity was predicted (?G = ?�14.3, Kd = 8.9E�?�11) when TRBV28 was replaced with TRBV20 paired with TRAV4 suggesting its role in CD predisposition. SNP rs12722069 at HLA-DQ8 that codes Arg76? forms three H-bonds with Glu12 and two H-bonds with Asn13 of DQ2 restricted gliadin in the presence of TRAV8-3/TRBV6. None of the HLA-DQ polymorphisms was found to be in linkage disequilibrium with reported CD susceptibility markers. Haplotypic presentations of rs12722069-G, rs1130392-C, rs3188043-C and rs4193-A with CD reported SNPs were observed in sub-ethnic groups. Highly polymorphic sites of HLA alleles and TCR variable regions could be utilized for better risk prediction models in CD. Therapeutic strategies by identifying inhibitors or blockers targeting specific gliadin:HLA-DQ:TCR binding sites could be investigated. � 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.Item Novel Eubacterium rectale inhibitor from Coriandrum sativum L. for possible prevention of colorectal cancer: a computational approach(Taylor and Francis Ltd., 2022-10-20T00:00:00) El Khatabi, Khalil; Kumar, Shashank; El-Mernissi, Reda; Singh, Atul Kumar; Ajana, Mohammed Aziz; Lakhlifi, Tahar; Bouachrine, MohammedThis research aims to screen out the effective bioactive compounds from Coriander (Coriandrum sativum L.), which may be novel potential inhibitors of Eubacterium rectale for the prevention of colorectal cancer (CRC). A series of 8 coriander-derived chemical compounds previously assessed for their anti-inflammatory, antioxidant, and antidiabetic activities were tested against Carbohydrate ABC transporter substrate-binding protein and compared to the standard inhibitor Acarbose, to support their use as novel Eubacterium rectale inhibitors. Herein, these derivatives were submitted to a thorough analysis of docking studies, in which detailed interactions of the selected phytocompounds with carbohydrate ABC transporter substrate-binding protein were revealed. Molecular docking analysis recommends Rutin, Gallocatechin, and Epigallocatechin as the most potential Eubacterium rectale inhibitors among the eight selected phytochemical compounds. Subsequently, the stability of the three selected phytochemical complexes was checked using molecular dynamics (MD) simulation at 100 ns and Molecular Mechanics combined with Poisson-Boltzmann Surface Area (MM-PBSA). The results show quite good stability for Rutin and Gallocatechin. In silico ADMET prediction was performed on the selected compounds, and the findings revealed a reasonably good ADMET profile for both Rutin and Gallocatechin. The current findings predict that Gallocatechin could be a better CRC preventive natural compound, and, further in�vitro, in�vivo and clinical studies may confirm its therapeutic potential. Communicated by Ramaswamy H. Sarma. � 2022 Informa UK Limited, trading as Taylor & Francis Group.Item Identification of Novel Indole Derivatives as Potent ?-Amylase Inhibitors for the Treatment of Type-II Diabetes Using in-Silico Approaches(AMG Transcend Association, 2022-04-09T00:00:00) Khatabi, Khalil El; El-Mernissi, Reda; Hajji, Halima; Singh, Atul Kumar; Ajana, Mohammed Aziz; Lakhlifi, Tahar; Kumar, Shashank; Bouachrine, MohammedThe ?-amylase is regarded as a promising drug target for diabetes mellitus-type II. Hence, inhibiting ?-amylase activity is a potential drug discovery approach for treating this chronic metabolic disorder. The present study explores the structural requirements and understands the inhibition mechanism of the novel developed indole-based derivatives as ?-amylase inhibitors through 3D-QSAR, molecular docking, ADMET, and molecular dynamics (MD) simulation. The 3D-QSAR study showed good statistical reliability for two developed predictive models; CoMFA and CoMSIA. Through a deep investigation of docking analysis, detailed interactions with ?-amylase of the most active compound 7 were explored. Four new indole derivatives were designed based on the contour maps and docking analysis, with significantly higher inhibitory activity than the molecules in the dataset. The selected molecules were evaluated for pharmacokinetic properties, showing a reasonably good ADMET profile. Furthermore, a 20-ns MD simulation of selected compounds bound to ?-amylase was performed to ensure stability during simulation further. Greater stability of the designed molecule-protein complex A1 was found. The present findings shed light on the binding mode and the interactions between newly designed compounds, especially compound A1 and ?-amylase and may be beneficial for drug development efforts targeting type-II diabetes. � 2022 by the authors.Item A candidate triple-negative breast cancer vaccine design by targeting clinically relevant cell surface markers: an integrated immuno and bio-informatics approach(Springer Science and Business Media Deutschland GmbH, 2022-02-20T00:00:00) Kumar, Shashank; Shuaib, Mohd; Prajapati, Kumari Sunita; Singh, Atul Kumar; Choudhary, Princy; Singh, Sangeeta; Gupta, SanjayTriple-negative breast cancer (TNBC) is an aggressive, metastatic/invasive sub-class of breast cancer (BCa). Cell surface protein-derived multi-epitope vaccine-mediated targeting of TNBC cells could be a better strategy against the disease. Literature-based identified potential cell surface markers for TNBC cells were subjected to expression pattern and survival analysis in BCa patient sample using TCGA database. The cytotoxic and helper T-lymphocytes antigenic epitopes in the test proteins were identified, selected and fused together with the appropriate linkers and an adjuvant, to construct the multi-epitope vaccine (MEV). The immune profile, physiochemical property (PP) and world population coverage of the MEV was studied. Immune simulation, cloning in a suitable vector, molecular docking (against Toll-like receptors, MHC (I/II) molecules), and molecular dynamics simulations of the MEV was performed. Cell surface markers were differentially expressed in TNBC samples and showed poor survival in TNBC patients. Satisfactory PP and WPC (up to 89 and 99%) was observed. MEV significant stable binding with the immune molecules and induced the immune cells in silico. The designed vaccine has capability to elicit immune response which could be utilized to target TNBC alone/combination with other therapy. The experimental studies are required to check the efficacy of the vaccine. � 2022, King Abdulaziz City for Science and Technology.Item Integrated 3D-QSAR, molecular docking, and molecular dynamics simulation studies on 1,2,3-triazole based derivatives for designing new acetylcholinesterase inhibitors(TUBITAK, 2021-02-14T00:00:00) EL KHATABI, Khalil; AANOUZ, Ilham; El-MERNISSI, Reda; SINGH, Atul Kumar; AJANA, Mohammed Aziz; LAKHLIFI, Tahar; KUMAR, Shashank; BOUACHRINE, MohammedAlzheimer's disease (AD) is a multifactorial and polygenic disease. It is the most prevalent reason for dementia in the aging population. A dataset of twenty-six 1,2,3-triazole-based derivatives previously synthetized and evaluated for acetylcholinesterase inhibitory activity were subjected to the three-dimensional quantitative structure-activity relationship (3D-QSAR) study. Good predictability was achieved for comparative molecular field analysis (CoMFA) (Q2 = 0.604, R2 = 0.863, rext2 = 0.701) and comparative molecular similarity indices analysis (CoMSIA) (Q2 = 0.606, R2 = 0.854, rext2 = 0.647). The molecular features characteristics provided by the 3D-QSAR contour plots were quite useful for designing and improving the activity of acetylcholinesterase of this class. Based on these findings, a new series of 1,2,3-triazole based derivatives were designed, among which compound A1 with the highest predictive activity was subjected to detailed molecular docking and compared to the most active compound. The selected compounds were further subjected to 20 ns molecular dynamics (MD) simulations to study the comparative conformation dynamics of the protein after ligand binding, revealing promising results for the designed molecule. Therefore, this study could provide worthy guidance for further experimental analysis of highly effective acetylcholinesterase inhibitors. � 2021 TUBITAK. All rights reserved.Item Novel potent inhibitors of Plasmodium vivax dihydrofolate reductase: An in silico antimalarial drug discovery(Association of Pharmaceutical Teachers of India, 2018) Pushpendra, Singh; Kushwaha, Prem Prakash; Shashank, KumarObjectives: In the present study, we targeted the dihydrofolate reductase enzyme that catalyzes the reduction of dihydrofolate to tetrahydrofolate which is required for the purines and pyrimidine synthesis. Malaria is one of the severe diseases throughout the world caused by blood-borne parasite Plasmodium vivax. Materials and Methods: Eighty-five parthenin analogs were docked against P. vivax and Homo sapiens dihydrofolate reductase proteins (PDB 2BL9 and 1KMS respectively) by using Maestro 9.6 program to evaluate the binding affinities of ligands with the protein. Results and Discussion: Docking analysis revealed some best hit ligands against P. vivax such as CID3467446 and CID56671343 but not inhibited the mammalian dihydrofolate reductase. The Dock score of parthenin analogs ranged from -7.31 to -9.3 while for standard dihydrofolate reductase inhibitors it was -4.78 to -8.04. Structural analysis of docked complexes of selected parthenin like compounds with P. vivax and mammalian dihydrofolate reductase revealed the involvement of Arg 115, Leu 136, Lys 138, Gly 175, Ser 117, Gln 177 and Ile 7, Ala 9, Thr 56, Ile 60, Pro 61 amino acid residues respectively in strong interactions. Absorption, distribution, metabolism, and excretion properties of best-docked compounds were predicted using QikProp application of Maestro 9.6. The results indicated that all the best-docked lead compounds followed Lipinski?s rule of five. Conclusion: Based on the results of the present study it has been concluded that parthenin like compounds may serve as potent dihydrofolate reductase inhibition based anti-malarial drug lead. ? 2018, Association of Pharmaceutical Teachers of India. All rights reserved.