Browsing by Author "Kumar, Shashank"

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Acarbose Potentially Binds to the Type I Peptide Deformylase Catalytic Site and Inhibits Bacterial Growth: An In Silico and In Vitro Study
(Bentham Science Publishers, 2022-09-23T00:00:00) Singh, Atul Kumar; Prajapati, Kumari Sunita; Kumar, Shashank
Background: In bacteria, peptide deformylase (PDF), a metalloenzyme, removes N-formyl methio-nine from a nascent protein, which is a critical step in the protein maturation process. The enzyme is ubiqui-tously present in bacteria and possesses therapeutic target potential. Acarbose, an FDA-approved antidiabetic drug, is an alpha-glucosidase inhibitor of microbial origin. Clinical studies indicate that acarbose administration in humans can alter gut microbiota. As per the best of our knowledge, the antibacterial potential of acarbose has not been reported. Objective: The present study aimed to check the binding ability of acarbose to the catalytic site of E. coli PDF and assess its in vitro antibacterial activity. Methods: Molecular docking, molecular dynamic (MD) simulation, and MM-PBSA experiments were per-formed to study the binding potential of the catalytic site, and a disc diffusion assay was also employed to assess the antibacterial potential of acarbose. Results: Acarbose was found to form a hydrogen bond and interact with the metal ion present at the catalytic site. The test compound showed a better docking score in comparison to the standard inhibitor of PDF. MD simulation results showed energetically stable acarbose-PDF complex formation in terms of RMSD, RMSF, Rg, SASA, and hydrogen bond formation throughout the simulation period compared to the actinonin-PDF complex. Furthermore, MM-PBSA calculations showed better binding free energy (?G) of acarbose PDF than the actinonin-PDF complex. Moreover, acarbose showed in vitro antibacterial activity. Conclusion: Acarbose forms conformational and thermodynamically stable interaction with the E. coli peptide deformylase catalytic site. Results of the present work necessitate in-depth antimicrobial potential studies on the effect of acarbose on drug resistance and nonresistant bacteria. � 2022 Bentham Science Publishers.
Ancistrobrevinium A, the first N-methylated, cationic naphthylisoquinoline alkaloid, from the tropical liana Ancistrocladus abbreviatus (Ancistrocladaceae)
(Taylor and Francis Ltd., 2023-03-29T00:00:00) Tajuddeen, Nasir; Fayez, Shaimaa; Kushwaha, Prem Prakash; Feineis, Doris; Ak� Assi, Laurent; Kumar, Shashank; Bringmann, Gerhard
Ancistrobrevinium A (1) is the first N-methylated and non-hydrogenated, and thus cationic naphthylisoquinoline alkaloid. It was discovered in the root bark extract of the phytochemically productive West African liana Ancistrocladus abbreviatus (Ancistrocladaceae). Its constitution was elucidated by HR-ESI-MS and 1D and 2D NMR. Due to the steric hindrance in the proximity of the linkage between the naphthalene and isoquinoline parts, the biaryl axis is rotationally hindered. It thus constitutes a stable element of chirality�the only one in the new alkaloid since, different from most other naphthylisoquinoline alkaloids, it has no stereogenic centers. The axial configuration of 1 was assigned by electronic circular dichroism (ECD) investigations, which gave a positive couplet, indicating a �positive chirality�, here corresponding to a P-configuration. Ancistrobrevinium A (1) showed a weak cytotoxic activity against A549 lung cancer cells (IC50 = 50.6 ?M). � 2023 Informa UK Limited, trading as Taylor & Francis Group.
Anti-proliferative, apoptosis inducing, and antioxidant potential of Callistemon lanceolatus bark extracts: an in vitro and in silico study
(Springer, 2023-05-08T00:00:00) Kumar, Ramesh; Kushwaha, Prem Prakash; Singh, Atul Kumar; Kumar, Shashank; Pandey, Abhay Kumar
The present study reports anticancer and antioxidant activities of Callistemon lanceolatus bark extracts. Anticancer activity was studied against MDA-MB-231 cells. Antioxidant assessment of the chloroform and methanol extracts showed considerable free radical scavenging, metal ion chelating, and reducing power potential. Chloroform extract exhibited potent inhibition of cancer cell proliferation in MTT assay (IC50 9.6�?g/ml) and promoted programmed cell death. Reactive oxygen species (ROS) generation, mitochondria membrane potential (MMP) disruption ability, and nuclear morphology changes were studied using H2-DCFDA, JC-1, and Hoechst dyes, respectively, using confocal microscopy. Apoptotic cells exhibited fragmented nuclei, increased ROS generation, and altered MMP in dose- and time-dependent manner. Chloroform extract upregulated the BAX-1 and CASP3 mRNA expression coupled with downregulation of BCL-2 gene. Further, in silico docking of phytochemicals present in C. lanceolatus with anti-apoptotic Bcl-2 protein endorsed apoptosis by its inhibition and thus corroborated the experimental findings. Obatoclax, a known inhibitor of Bcl-2 was used as a reference compounds. � 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Assessment of Antioxidant Potential of Dietary Components
(Elsevier, 2017) Kumar, Shashank; Chaitanya, Rapalli Krishna; Preedy, Victor R.
Antioxidants neutralize or mitigate the harmful effects of free radicals. Such antioxidants may be classed as either enzymatic or nonenzymatic. Some components in the diet act as important antioxidants as they may have direct antioxidant activity or are a component of antioxidant systems. Free radical-mediated stress arises when body fails to ameliorate the excess generation of free radicals. In such circumstances the need for supplementary or other dietary antioxidants arises. As a consequence, it is necessary to assay antioxidants status in subjects or antioxidant potential of novel dietary components. Several techniques have been developed to measure the antioxidant potential of dietary components. We describe antioxidants in general, then various platforms using spectroscopic, chromatographic, electrochemical, and photochemical methods. The following in assays and protocols are reviewed: hydrogen atom transfer, oxygen radical absorbance capacity, diphenyl-1-picrylhydrazyl radical scavenging, trolox equivalent antioxidant capacity, ferric-reducing antioxidant power, total radical-trapping antioxidant parameter, metal-chelating capacity, hydroxyl radical antioxidant capacity, diene conjugates, thiobarbituric acid reactive substances, hexanal, 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid, phycoerythrin, bleomycin-iron, copper-1,10-phenanthroline complex, peroxynitrite, lipid-soluble antioxidants, beta-carotene bleaching, hydroxyl radical scavenging, superoxide anion radical scavenging capacity, ferrous oxidation-xylenol orange, ferric thiocyanate, nonenzymatic in vivo and enzymatic in vivo assays. ? 2018 Elsevier Inc. All rights reserved.
Association of MTHFR (C677T) Gene Polymorphism With Breast Cancer in North India
(Sage, 2016) Waseem, Mohammad; Hussain, Syed Rizwan; Kumar, Shashank; Serajuddin, Mohammad; Mahdi, Farzana; Sonkar, Satyendra Kumar; Bansal, Chery; Ahmad, Mohammad Kaleem
Background Breast cancer is one of the most common malignancies in women and is associated with a variety of risk factors. The functional single-nucleotide polymorphism (SNP) C677T in the gene encoding 5,10-methylenetetrahydrofolate reductase (MTHFR) may lead to decreased enzyme activity and affect the chemosensitivity of tumor cells. This study was designed to investigate the association of MTHFR gene polymorphism (SNP) in the pathogenesis of breast cancer among the North Indian women population. Materials and Methods Genotyping was performed by polymerase chain reaction (PCR) using genomic DNA, extracted from the peripheral blood of subjects with (275 cases) or without (275 controls) breast cancer. Restriction fragment length polymorphism was used to study C677T polymorphism in the study groups. Results The distribution of MTHFR (C677T) genotype frequencies, ie, CC, TT, and CT, among the patients was 64.7%, 2.18%, and 33.09%, respectively. In the healthy control group, the CC, TT, and CT frequencies were 78.91%, 1.09%, and 20.1%, respectively. The frequencies of C and T alleles were 81.2% and 18.7%, respectively, in the patient subjects, while they were 88.9% and 11.09%, respectively, among the healthy control group. Frequencies of the CT genotype and the T allele were significantly different (P= 0.007 and P = 0.005, respectively) between the control and the case subjects. Conclusion This study shows an association of the CT genotype and the T allele of the MTHFR (C667T) gene with increased genetic risk for breast cancer among Indian women.
Bioinformatics insights into CENP-T and CENP-W protein-protein interaction disruptive amino acid substitution in the CENP-T-W complex
(John Wiley and Sons Inc, 2023-11-09T00:00:00) Mohanty, Suryakanta; Bhadane, Rajendra; Kumar, Shashank
Kinetochores are multi-protein assemblies present at the centromere of the human chromosome and play a crucial role in cellular mitosis. The CENP-T and CENP-W chains form a heterodimer, which is an integral part of the inner kinetochore, interacting with the linker DNA on one side and the outer kinetochore on the other. Additionally, the CENP-T-W dimer interacts with other regulatory proteins involved in forming inner kinetochores. The specific roles of different amino acids in the CENP-W at the protein-protein interaction (PPI) interface during the CENP-T-W dimer formation remain incompletely understood. Since cell division goes awry in diseases like cancer, this CENP-T-W partnership is a potential target for new drugs that could restore healthy cell division. We employed molecular docking, binding free energy calculations, and molecular dynamics (MD) simulations to investigate the disruptive effects of amino acids substitutions in the CENP-W chain on CENP-T-W dimer formation. By conducting a molecular docking study and analysing hydrogen bonding interactions, we identified key residues in CENP-W (ASN-46, ARG-53, LEU-83, SER-86, ARG-87, and GLY-88) for further investigation. Through site-directed mutagenesis and subsequent binding free energy calculations, we refined the selection of mutant. We chose four mutants (N46K, R53K, L83K, and R87E) of CENP-W to assess their comparative potential in forming CENP-T-W dimer. Our analysis from 250 ns long revealed that the substitution of LEU83 and ARG53 residues in CENP-W with the LYS significantly disrupts the formation of CENP-T-W dimer. In conclusion, LEU83 and ARG53 play a critical role in CENP-T and CENP-W dimerization which is ultimately required for cellular mitosis. Our findings not only deepen our understanding of cell division but also hint at exciting drug-target possibilities. � 2023 The Authors. Journal of Cellular Biochemistry published by Wiley Periodicals LLC.
Biological/Biosimilar Drugs: A New Hope for Better and Low Cost Treatment
(Juniper Publishers, 2016) Kumar, Shashank
Biological and biosimilar drugs Medicines that are derived from living cells/organisms are known as biological medicines. They consist of of highly complex molecular entities difficult to characterize. Certain degree of variations might found among biological medicines due to variation of the biological system and manufacturing process. A medicine that is very similar and clinically equivalent to a biological medicine is known as biosimilar medicine. Reference or originator medicine is an already approved biological medicine from which a biosimilar active medicine is derived. The biological product is highly similar to the reference product not withstanding minor differences in clinically inactive components; and there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency of the product. Biosimilar medicines are not the same as generic medicines, which contain simpler chemical structures and are identical, in terms of molecular structure, to their reference drugs [1].
Bulbine frutescens phytochemicals as novel ABC-transporter inhibitor: A molecular docking and molecular dynamics simulation study
(OAE Publishing Inc., 2021-01-08T00:00:00) Kushwaha, Prem Prakash; Maurya, Santosh Kumar; Singh, Amit; Prajapati, Kumari Sunita; Singh, Atul Kumar; Shuaib, Mohd; Kumar, Shashank
Aim: The present in silico study aimed to evaluate the ATP-binding cassette (ABC) transporter inhibition potential of Bulbine frutescens (B. frutescens) phytochemicals. Methods: Several previous studies and databases were used to retrieve the ligands and target protein structure. The molecular docking study was performed using the Auto Dock Tools, and the GROMACS package was applied to accomplish molecular dynamics simulation. Results: Utilizing the molecular docking and simulation approach, ?25 phytochemicals were screened against the ABC transporter protein. Docking score analysis revealed that B. frutescens phytochemical 4?-Demethylknipholone 2?-?-D-glucopyranoside exhibited strong binding on the ABC transporter protein with a minimum binding score -9.8 kcal/mol in comparison to the standard ABC transporter inhibitor diltiazem (-6.86 kcal/mol). Furthermore, molecular dynamics simulation for 4?-Demethylknipholone 2?-?-D-glucopyranoside showed an acceptable root mean square deviation, radius of gyration, root mean square fluctuation, and hydrogen bond, in addition to other lead compounds. Conclusion: The in-silico study demonstrated that B. frutescens phytochemical 4?-Demethylknipholone 2?-?-D-glucopyranoside possesses anti-drug resistance properties and requires further testing in preclinical settings. � 2021 The Author(s).
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, Sanjay
Triple-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.
Characterization of phytochemicals and validation of antioxidant and anticancer activity in some Indian polyherbal ayurvedic products
(Springer, 2021-03-13T00:00:00) Kushwaha, Prem Prakash; Kumar, Ramesh; Neog, Panchi Rani; Behara, Malay Ranjan; Singh, Pratibha; Kumar, Ajay; Prajapati, Kumari Sunita; Singh, Atul Kumar; Shuaib, Mohd; Sharma, Amit Kumar; Pandey, Abhay Kumar; Kumar, Shashank
In the present comparative study, the authors studied the antioxidant and anticancer activity of commercially available polyherbal Indian Ayurvedic products namely Divya Sarvakalp Kwath (DSKK), Divya Sanjivani Vati (DSV), Kanchanar Guggulu (KG) and Shakti Drop (SD). Authors also quantified phenolic and flavonoid contents in the samples. Solid powdered samples (DSKK, DSV, and KG) were extracted in methanol and water (1:1) using cold extraction method. Spectrophotometry technique was used to quantify the phytochemicals present in test samples. DSKK showed comparatively higher content of total phenolics (247.65 � 0.05 ?gPGE/g) and flavonoid (34.66 � 0.19 �gQE/mg). Radical scavenging, metal ion chelation and reducing potential of test products were studied using nitric oxide scavenging, DPPH, metal ion chelation, reducing power ability, and phosphomolybdate in vitro antioxidant assays at different concentration. Dose-dependent antioxidant activity was observed in all the test samples at 100�500��g or �l/ml concentration. Anticancer efficacy of the test samples were studied in lung (A549), colon (Colo205), and breast cancer (MCF7) cell lines at different concentrations (10�100��g or �l/ml) using MTT assay. Confocal microscopy was used to reveal the apoptotic induction, mitochondrial membrane integrity disruption and reactive oxygen species production ability of test products in cancer cells. The present study revealed that DSKK possesses comparatively better antioxidant potential and SD has potent anticancer activity against breast cancer cells. � 2021, Society for Plant Research.
Contributions of human ACE2 and TMPRSS2 in determining host�pathogen interaction of COVID-19
(Springer, 2021-02-25T00:00:00) Senapati, Sabyasachi; Banerjee, Pratibha; Bhagavatula, Sandilya; Kushwaha, Prem Prakash; Kumar, Shashank
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is at present an emerging global public health crisis. Angiotensin converting enzyme 2 (ACE2) and trans-membrane protease serine 2 (TMPRSS2) are the two major host factors that contribute to the virulence of SARS-CoV-2 and pathogenesis of coronavirus disease-19 (COVID-19). Transmission of SARS-CoV-2 from animal to human is considered a rare event that necessarily requires strong evolutionary adaptations. Till date no other human cellular receptors are identified beside ACE2 for SARS-CoV-2 entry inside the human cell. Proteolytic cleavage of viral spike (S)-protein and ACE2 by TMPRSS2 began the entire host�pathogen interaction initiated with the physical binding of ACE2 to S-protein. SARS-CoV-2 S-protein binds to ACE2 with much higher affinity and stability than that of SARS-CoVs. Molecular interactions between ACE2-S and TMPRSS2-S are crucial and preciously mediated by specific residues. Structural stability, binding affinity and level of expression of these three interacting proteins are key susceptibility factors for COVID-19. Specific protein�protein interactions (PPI) are being identified that explains uniqueness of SARS-CoV-2 infection. Amino acid substitutions due to naturally occurring genetic polymorphisms potentially alter these PPIs and poses further clinical heterogeneity of COVID-19. Repurposing of several phytochemicals and approved drugs against ACE2, TMPRSS2 and S-protein have been proposed that could inhibit PPI between them. We have also identified some novel lead phytochemicals present in Azadirachta indica and Aloe barbadensis which could be utilized for further in vitro and in vivo anti-COVID-19 drug discovery. Uncovering details of ACE2-S and TMPRSS2-S interactions would further contribute to future research on COVID-19. � 2021, Indian Academy of Sciences.
Current therapeutic modalities and chemopreventive role of natural products in liver cancer: Progress and promise
(Baishideng Publishing Group Inc, 2023-01-15T00:00:00) Singh, Amit Kumar; Singh, Shiv Vardan; Kumar, Ramesh; Kumar, Shashank; Senapati, Sabyasachi; Pandey, Abhay K
Liver cancer is a severe concern for public health officials since the clinical cases are increasing each year, with an estimated 5-year survival rate of 30%�35% after diagnosis. Hepatocellular carcinoma (HCC) constitutes a significant subtype of liver cancer (approximate75%) and is considered primary liver cancer. Treatment for liver cancer mainly depends on the stage of its progression, where surgery including, hepatectomy and liver transplantation, and ablation and radiotherapy are the prime choice. For advanced liver cancer, various drugs and immunotherapy are used as first-line treatment, whereas second-line treatment includes chemotherapeutic drugs from natural and synthetic origins. Sorafenib and lenvatinib are first-line therapies, while regorafenib and ramucirumab are secondline therapy. Various metabolic and signaling pathways such as Notch, JAK/ STAT, Hippo, TGF-?, and Wnt have played a critical role during HCC progression. Dysbiosis has also been implicated in liver cancer. Drug-induced toxicity is a key obstacle in the treatment of liver cancer, necessitating the development of effective and safe medications, with natural compounds such as resveratrol, curcumin, diallyl sulfide, and others emerging as promising anticancer agents. This review highlights the current status of liver cancer research, signaling pathways, therapeutic targets, current treatment strategies and the chemopreventive role of various natural products in managing liver cancer � The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved
D Allele Frequency in Insertion/Deletion Polymorphism of the Angiotensin Converting Enzyme (ACE) Gene is Associated with Development of Breast Cancer Risk in Indian Women
(Bentham Science, 2016) Kumar, Shashank; Hussain, Syed Rizwan; Waseem, Mohammad; Mahdi, Farzana; Bansal, Chery; Ahmad, Mohammad Kaleem
Aims: Breast cancer is the second most common cancer in the world and, by far, the most frequent cancer among women. Scientific literature has hypothesized the association of ACE I/D polymorphism with breast cancer for several decades. Unfortunately the outcomes of studies are inconsistent. Thus the present study was designed to evaluate the association of ACE gene (I/D) polymorphism with breast cancer in Indian population. Methods: Genotyping was performed by PCR (polymerase chain reaction), using genomic DNA extracted from peripheral blood of subjects, with (213 cases) or without (213 controls) breast cancer. Findings: The distribution of ACE genotype frequencies i.e. II, DD and ID in patients was 43.19%, 16.43% and 40.38% respectively. In healthy control group II, DD and ID frequencies were 52.58%, 11.27% and 36.15% respectively. The frequencies of D and I alleles were 29.34% and 70.66% in the healthy subjects, while 36.62% and 63.38% among the patient group. Frequency of D allele was significantly different (p=0.0287) between control and case subjects. Significance: The present study showed an association of D allele of ACE gene with increased genetic risk factor for breast cancer in Indian women. 0.2% increased disease risk was found in patients carrying D allele.
Designing of neoepitopes based vaccine against breast cancer using integrated immuno and bioinformatics approach
(Taylor and Francis Ltd., 2023-08-16T00:00:00) Shuaib, Mohd; Singh, Atul Kumar; Gupta, Sanjay; Alasmari, Abdullah F.; Alqahtani, Flaeh; Kumar, Shashank
Cancer is characterized by genetic instability due to accumulation of somatic mutations in the genes which generate neoepitopes (mutated epitopes) for targeting by Cytotoxic T lymphocytes (CTL). Breast cancer has a high transformation rate with unique composition of mutational burden and neoepitopes load that open a platform to designing a neoepitopes-based vaccine. Neoepitopes-based therapeutic cancer vaccines designed by neoantigens have shown to be feasible, nontoxic, and immunogenic in cancer patients. Stimulation of CTL by neoepitope-based vaccine of self-antigenic proteins plays a key role in distinguishing cancer cells from normal cells and selectively targets only malignant cells. A neoepitopes-based vaccine to combat breast cancer was designed by combining immunology and bioinformatics approaches. The vaccine construct was assembled by the fusion of CTL neoepitopes, helper sequences (used for better separation of the epitopes), and adjuvant together with linkers. The neoepitopes were identified from somatic mutations in the MUC16, TP53, RYR2, F5, DNAH17, ASPM, and ABCA13 self-antigenic proteins. The vaccine construct was undertaken to study the immune simulations (IS), physiochemical characteristics (PP), molecular docking (MD) and simulations, and cloning in appropriate vector. Together, these parameters establish safety, stability, and a strong binding affinity against class I MHC molecules capable of inducing a complete immune response against breast cancer cells. Communicated by Ramaswamy H. Sarma. � 2023 Informa UK Limited, trading as Taylor & Francis Group.
Discovery of differentially expressed novel miRNAs in breast normal cells and their putative targets
(Springer, 2023-01-21T00:00:00) Shuaib, Mohd; Prajapati, Kumari Sunita; Singh, Atul Kumar; Kumar, Shashank
MicroRNAs (miRNAs) play critical role in normal breast development and their altered expression may lead to breast cancer. Identification of new miRNAs allows us to understand the normal physiological process and associated disease pathophysiology. In the present study we identify the novel miRNAs in withaferin A treated breast normal cells (MCF-10A) using small RNA sequencing. The pathophysiological potential of the identified miRNAs was checked by studying their expression pattern in MDA-MB-231 and MCF-7 breast cancer cells using qRT-PCR technique. The secondary/tertiary structure of the identified miRNAs, target gene enrichment in Gene Ontology terms and KEGG pathway, miRNA-mRNA interaction of the sorted target genes, miRNA-mRNA/miRNA-argonaute protein/miRNA-mRNA-argonaute protein interaction and stability, were studied using bioinformatics tools/software, and molecular dynamics simulations. Hsa-miR-N88585 and hsa-miR-N461089 were identified and validated as novel miRNAs in normal breast cells. Up-expression of identified miRNAs in MDA-MB-231 and MCF-7 cells indicates their oncogenic nature. Identified target genes were enriched in classical signaling pathways (AMPK and Ras) and important GO terms. PLXDC2, BHLHE40, ARMC8, and PECAM1, CDC27, KCNK3 genes were sorted as putative targets for hsa-miR-N88585 and hsa-miR-N461089, respectively. MD simulation revealed stable hsa-miR-N88585/hsa-miR-N461089-AGO protein complex formation which indicates their further processing. In conclusion, the study identifies hsa-miR-N88585 and hsa-miR-N461089 as novel miRNAs in breast normal cells which are significantly inversely expressed in breast cancer cells. Further experiments are required to study the role of identified novel miRNAs in normal breast development and pathophysiology of breast cancer. Graphical abstract: [Figure not available: see fulltext.]. � 2023, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
Discovery of Natural Anti-Apoptotic Protein Inhibitor Using Molecular Docking and MM-GBSA Approach: An Anticancer Intervention
(AMG Transcend Association, 2022-12-27T00:00:00) Dey, Sarbjit; Singh, Atul Kumar; Kumar, Shashank
Apoptosis is a programmed molecular phenomenon in normal cells, and "evading apoptosis" is a hallmark of cancer. Overexpression of anti-apoptotic BCL-2 promotes cancer cell survival, leading to tumor formation, its maintenance and progression, and further chemoresistance. Therefore, BCL-2 is considered an exciting drug target in clinical studies. The Cip/Kip family protein p21, which acts as an inhibitor of cyclin-CDK complexes, can also exert anti-apoptotic function and thus be involved in cancer initiation and progression. Preliminary research suggests that Piper chaba phytochemical(s) possess anticancer activity, but the underlying mechanism is yet to be established. For the first time, we explored Piper chaba phytochemicals for their anti-apoptotic protein (BCL-2 and p21) inhibition potential using molecular docking and MM-GBSA experiments. UC2288 and Venetoclax were known standards for BCL-2 and p21 proteins, respectively. We also explored the pharmacokinetics and drug-likeness properties of lead molecules using the SwissADME web tool. A total of 45 P. chaba phytochemicals were identified from published literature and docked at the drug-binding site of target proteins. Chabamide F, Piperchabaoside B, Piperundecalidiene, and Chabamide G showed ? binding affinity (-9.0 kcal/mole) than UC2288, while Brachystamide B showed lower binding affinity (-9.7 kcal/mole) than Venetoclax. MM-GBSA results revealed Chabamide F has a higher binding affinity for p21 than the standard compound. Therefore, P. chaba phytoconstituents qualify for further experiments on the drug discovery process to target anti-apoptosis proteins in cancer cells. � 2022 by the authors.
Drug Resistance Mechanism of M46I-Mutation-Induced Saquinavir Resistance in HIV-1 Protease Using Molecular Dynamics Simulation and Binding Energy Calculation
(MDPI, 2022-03-30T00:00:00) Rana, Nilottam; Singh, Atul Kumar; Shuaib, Mohd; Gupta, Sanjay; Habiballah, Mahmoud M.; Alkhanani, Mustfa F.; Haque, Shafiul; Reshi, Mohd Salim; Kumar, Shashank
Drug-resistance-associated mutation in essential proteins of the viral life cycle is a major concern in anti-retroviral therapy. M46I, a non-active site mutation in HIV-1 protease has been clinically associated with saquinavir resistance in HIV patients. A 100 ns molecular dynamics (MD) simulation and MM-PBSA calculations were performed to study the molecular mechanism of M46I-mutation-based saquinavir resistance. In order to acquire deeper insight into the drug-resistance mechanism, the flap curling, closed/semi-open/open conformations, and active site compactness were studied. The M46I mutation significantly affects the energetics and conformational stability of HIV-1 protease in terms of RMSD, RMSF, Rg, SASA, and hydrogen formation potential. This mutation significantly decreased van der Waals interaction and binding free energy (?G) in the M46I�saquinavir complex and induced inward flap curling and a wider opening of the flaps for most of the MD simulation period. The predominant open conformation was reduced, but inward flap curling/active site compactness was increased in the presence of saquinavir in M46I HIV-1 protease. In conclusion, the M46I mutation induced structural dynamics changes that weaken the protease grip on saquinavir without distorting the active site of the protein. The produced information may be utilized for the discovery of inhibitor(s) against drug-resistant HIV-1 protease. � 2022 by the authors. Licensee MDPI, Basel, Switzerland.
Five-Decade Update on Chemopreventive and Other Pharmacological Potential of Kurarinone: a Natural Flavanone
(Frontiers Media S.A., 2021-09-27T00:00:00) Kumar, Shashank; Prajapati, Kumari Sunita; Shuaib, Mohd; Kushwaha, Prem Prakash; Tuli, Hardeep Singh; Singh, Atul Kumar
In the present article we present an update on the role of chemoprevention and other pharmacological activities reported on kurarinone, a natural flavanone (from 1970 to 2021). To the best of our knowledge this is the first and exhaustive review of kurarinone. The literature was obtained from different search engine platforms including PubMed. Kurarinone possesses anticancer potential against cervical, lung (non-small and small), hepatic, esophageal, breast, gastric, cervical, and prostate cancer cells. In vivo anticancer potential of kurarinone has been extensively studied in lungs (non-small and small) using experimental xenograft models. In in vitro anticancer studies, kurarinone showed IC50 in the range of 2�62��M while in vivo efficacy was studied in the range of 20�500�mg/kg body weight of the experimental organism. The phytochemical showed higher selectivity toward cancer cells in comparison to respective normal cells. kurarinone inhibits cell cycle progression in G2/M and Sub-G1 phase in a cancer-specific context. It induces apoptosis in cancer cells by modulating molecular players involved in apoptosis/anti-apoptotic processes such as NF-?B, caspase 3/8/9/12, Bcl2, Bcl-XL, etc. The phytochemical inhibits metastasis in cancer cells by modulating the protein expression of Vimentin, N-cadherin, E-cadherin, MMP2, MMP3, and MMP9. It produces a cytostatic effect by modulating p21, p27, Cyclin D1, and Cyclin A proteins in cancer cells. Kurarinone possesses stress-mediated anticancer activity and modulates STAT3 and Akt pathways. Besides, the literature showed that kurarinone possesses anti-inflammatory, anti-drug resistance, anti-microbial (fungal, yeast, bacteria, and Coronavirus), channel and transporter modulation, neuroprotection, and estrogenic activities as well as tyrosinase/diacylglycerol acyltransferase/glucosidase/aldose reductase/human carboxylesterases 2 inhibitory potential. Kurarinone also showed therapeutic potential in the clinical study. Further, we also discussed the isolation, bioavailability, metabolism, and toxicity of Kurarinone in experimental models. � Copyright � 2021 Kumar, Prajapati, Shuaib, Kushwaha, Tuli and Singh.
Flavonoids as emerging notch signaling pathway modulators in cancer
(Taylor and Francis Ltd., 2023-04-21T00:00:00) Singh, Atul Kumar; Kumar, Shashank
Notch signaling is an evolutionary conserved pathway important for the developmental processes and implicated in the tumor formation. Notch signaling pathway (NSP) inhibitors have been tested in clinical trials alone or in combination with the chemotherapy but none got clinical approval due to severe toxicity in patients. Flavonoids inhibit NSP by inhibiting notch receptor cleavage and/or inhibiting transcriptional regulation by Notch intracellular domain (NICD). Interestingly, some flavonoids are reported to inhibit NSP by mediating the microRNA expression. NSP inhibitory flavonoid(s) in combination with standard therapy is might be an effective strategy in cancer treatment. � 2023 Informa UK Limited, trading as Taylor & Francis Group.
Flavonols as cancer preventive agents: Recent updates
(Nova Science Publishers, Inc., 2021-06-20T00:00:00) Kumar, Shashank; Singh, Pushpendra
This book describes primary results on the leading edge of in silico and in vitro cancer research and summarizes the anticancer activity of pharmacologically important flavonols such as quercetin, morin, kaempferol, fisetin, galangin, diosmetin, and cianidanol. Natural products are a prime source of lead compounds suitable for further modification during drug development. Cancer drug discovery is a risky, costly, and resource-consuming process. In the modern arena, molecular computer modeling in anticancer drug development is utilized to speed up hit identification and optimization of the pharmacological profile. The first chapter of this book deals with computer-aided drug discovery and anticancer drug design using pharmacological active flavonols. In further chapters, the authors discuss the in vitro and in vivo advancement in anticancer research on important flavonols such as quercetin, morin, kaempferol, fisetin, galangin, diosmetin, and cianidanol. Anticancer advancement research related to various cancers is summarized and discussed, giving special emphasis on the effect on apoptosis, migrations, and growth via various signaling pathways. The book encompasses the literature as well as target identification for the selected flavonols for their in silico anticancer potential. Moreover, it also contains experimentation results and discussion on the pharmacological properties, including ADME/T, of the flavonols. Overall, this book can lay a good basis for the subsequent rise for its application as a therapeutic drug in the near future. � 2021 by Nova Science Publishers, Inc. All rights reserved.