Rajnish Kumar

Indian Institute of Technology BHU

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Anurag T. K. Baidya

Academy of Scientific and Innovative Research

Taher Darreh‐Shori

Karolinska Institutet

Bhanuranjan Das

Indian Institute of Technology BHU

Bharti Devi

Central University of Punjab

Pavel F. Pavlov

Karolinska Institutet

Bengt Winblad

Karolinska Institutet

Amit Kumar

Karolinska Institutet

Manoj Kumar

Stanford University

Lisha Wang

Ministry of Agriculture and Rural Affairs

Manoj Kumar Mahapatra

National Institute of Technology Rourkela

Cooperative Institutions

Banaras Hindu University

Panjab University

Indian Institute of Technology BHU

Karolinska Institutet

Jaypee Institute of Information Technology

Indian Institute of Technology Indore

University of Delhi

Karolinska University Hospital

All India Institute of Medical Sciences

Maharaja Sayajirao University of Baroda

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Hydroxytyrosol as anti-parkinsonian molecule: Assessment using in-silico and MPTP-induced Parkinson’s disease model

Biomedicine & Pharmacotherapy (2021)

Anjana Pathania Rajnish Kumar Rajat Sandhir

3-Hydroxytyrosol (HXT) is a natural polyphenol present in extra virgin olive oil. It is a key component of Mediterranean diet and is known for its strong antioxidant activity. The present study evaluated the potential of HXT as an anti-parkinsonian molecule in terms of its ability to inhibit MAO-B and thereby maintaining dopamine (DA) levels in Parkinson's disease (PD). In-silico molecular docking study followed by MMGBSA binding free energy calculation revealed that HXT has a strong binding affinity for MAO-B in comparison to MAO-A. Moreover, rasagiline and HXT interacted with the similar binding sites and modes of interactions. Additionally, molecular dynamics simulation studies revealed stable nature of HXT-MAO-B interaction and also provided information about the amino acid residues involved in binding. Moreover, in vitro studies revealed that HXT inhibited MAO-B in human platelets with IC50 value of 7.78 μM. In vivo studies using MPTP-induced mouse model of PD revealed increase in DA levels with concomitant decrease in DA metabolites (DOPAC and HVA) on HXT treatment. Furthermore, MAO-B activity was also inhibited on HXT administration to PD mice. In addition, HXT treatment prevented MPTP-induced loss of DA neurons in substantia nigra and their nerve terminals in the striatum. HXT also attenuated motor impairments in PD mice assessed by catalepsy bar, narrow beam walk and open field tests. Thus, the present findings reveal HXT as a potential inhibitor of MAO-B, which may be used as a lead molecule for the development of therapeutics for PD.

MPTP

Monoamine oxidase B

10.1016/j.biopha.2021.111525

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Citations (16)

FKBP51-Hsp90 Interaction-Deficient Mice Exhibit Altered Endocrine Stress Response and Sex Differences Under High-Fat Diet

Molecular Neurobiology (2023)

Lisha Wang Jakub Wojcieszak Rajnish Kumar Zhe Zhao Xuelian Sun

FK506-binding protein 51 kDa (FKBP51), encoded by Fkbp5 gene, gained considerable attention as an important regulator of several aspects of human biology including stress response, metabolic dysfunction, inflammation, and age-dependent neurodegeneration. Its catalytic peptidyl-prolyl isomerase (PPIase) activity is mediated by the N-terminal FK506-binding (FK1) domain, whereas the C-terminal tetratricopeptide motif (TPR) domain is responsible for FKBP51 interaction with molecular chaperone heat shock protein 90 (Hsp90). To understand FKBP51-related biology, several mouse models have been created. These include Fkbp5 complete and conditional knockouts, overexpression, and humanized models. To dissect the role of FKBP51-Hsp90 interaction in FKBP51 biology, we have created an interaction-deficient mouse (Fkbp5

Tetratricopeptide

Corticosterone

Cellular stress response

Wild type

10.1007/s12035-023-03627-x

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Citations (1)

Structural modification aimed for improving solubility of lead compounds in early phase drug discovery

Bioorganic & Medicinal Chemistry (2022)

Bhanuranjan Das Anurag T. K. Baidya Alen T. Mathew Ashok Kumar Yadav Rajnish Kumar

Drug Development

10.1016/j.bmc.2022.116614

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Citations (88)

Artificial intelligence assisted identification of potential tau aggregation inhibitors: ligand- and structure-based virtual screening, in silico ADME, and molecular dynamics study

Molecular Diversity (2023)

Bhanuranjan Das Alen T. Mathew Anurag T. K. Baidya Bharti Devi Rahul Rampa Salmon

ADME

Docking (animal)

Binding potential

10.1007/s11030-023-10645-3

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Citations (8)

Exploration of Novel Lichen Compounds as Inhibitors of SARS-CoV-2 Mpro: Ligand-Based Design, Molecular Dynamics, and ADMET Analyses

Applied Biochemistry and Biotechnology (2022)

Amit Gupta Niharika Sahu Ashish P. Singh Vinay Kumar Singh Suresh C. Singh

2019-20 coronavirus outbreak

10.1007/s12010-022-04103-3

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Citations (20)

O5‐06‐06: LIGANDS OF THE CORE ACETYLCHOLINE BIOSYNTHESIZING ENZYME, CHOLINE ACETYLTRANSFERASE, AS NOVEL AND POTENTIAL THERAPEUTIC AGENTS AND IN VIVO PET TRACERS FOR EARLY DIAGNOSIS OF ALZHEIMER'S DISEASE

Alzheimer s & Dementia (2019)

Taher Darreh‐Shori Rajnish Kumar Amit Kumar Prashant R. Murumkar Sangram Nag

A key feature of Alzheimer's disease (AD) is an early and severe degeneration of the cholinergic projections throughout the brain. This characteristic is also shared by Lewy Body Dementia, Parkinson's disease dementia and Down's syndrome. Expression of the core acetylcholine (ACh) biosynthesizing enzyme, choline acetyltransferase (ChAT) defines this widespread neuronal system. Thereby ChAT was chosen as a prominent target for developing new in vivo probes for mapping cholinergic network, and designing novel cholinergic enhancing therapeutic agents. Advanced in silico molecular modelling analysis was used to screen diverse drug registries and an in-house molecular library against ChAT. The in silico hits were then examined with a robust in-house invented high-throughput ChAT assays using human recombinant protein and postmortem tissue extracts of 3 different brain regions of a group of AD (n=6) and controls (n=6). All hits were also tested against ACh degrading enzymes, AChE and BChE. We identified two different class of ChAT ligands. One class acted as highly potent inhibitor of ChAT, with low nanomolar activity. They show negligible activity against ACh degrading enzymes, indicating high selectivity for ChAT. The second class, on the contrary enhanced the intrinsic catalytic rate of ACh-biosynthesis by ChAT. These compounds compose the first ever identified small molecules, and are termed by us as ChAT Potentiating Ligands (CPLs). Systematic enzymes kinetic analyses identified 10 CPLs with EC50 values in low micromolar ranges. Some of CPLs also acted on AChE and/or BChE but as inhibitors. These are hence expected to exhibit a potentially dual mode of cholinergic enhancing actions of both increasing the biosynthesis of ACh, and inhibiting its degradation. Given the early and selective degeneration of the central cholinergic neurons in the major dementia disorders and ChAT being the defining marker of this neuronal system, the high affinity and selective ChAT inhibitors are being tested as ChAT-PET tracer. The CPLs on the other hand constitute a novel class of compounds of cholinergic enhancing agents that act by increasing biosynthesis of acetylcholine rather than preventing its degradation. They are hence expected to show superior efficacy than the currently in use cholinesterase inhibitors.

10.1016/j.jalz.2019.06.4869

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Citations (1)

Characterization, DFT study and evaluation of antioxidant potentials of mycosporine-like amino acids (MAAs) in the cyanobacterium Anabaenopsis circularis HKAR-22

Journal of Photochemistry and Photobiology B Biology (2024)

Varsha K. Singh Bhanuranjan Das Sapana Jha Palak Rana Rajnish Kumar

Photosynthetically active radiation

Ultraviolet

10.1016/j.jphotobiol.2024.112975

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Citations (1)

Unveiling of Indanone‐Benzimidazole Hybrids as Anti‐Alzheimer's Agents: Computational and Experimental Studies

ChemistrySelect (2024)

Pragati Kushwaha Bhanuranjan Das Rajnish Kumar

Abstract The growing concern of Alzheimer's disease underscores the urgent requirement for the development of novel therapeutic agents. In this study, a series of 15 hybrid molecules containing Indanone‐Benzimidazole heterocycles were designed utilizing the molecular hybridization approach. The synthesized molecules were characterized by spectroscopic techniques and their anti‐Alzheimer's behaviour were examined. Biological assessment demonstrated that compounds 14 and 15 exhibited significant reduction of “human” amyloid beta (A β ) peptide aggregation, expressing on transgenic Caenorhabditis elegans ( C. elegans ) strain CL4176. These compounds were further evaluated for their AChE inhibitory effects in transgenic C. elegans strain CL2006 and found significant. Molecular docking investigations have elucidated the commendable affinity exhibited by the studied ligands towards the A β pentamer (PDB: 2BEG) and acetylcholinesterase (AChE) (PDB: 4EY7). Subsequent to these docking studies, molecular dynamics simulations were conducted, affirming the stability of both ligands in association with the A β pentamer and ACh. Additionally, Density functional theory (DFT) calculations were performed by using B3LYP energy level with the basis set 6–311 G (d, p) basis set to correlate with experimental results. Taken together, all these findings evidenced the experimental results and this study sheds light on the anti‐Alzheimer's potential of Indanone‐Benzimidazole hybrids.

Pentamer

Benzimidazole

Docking (animal)

10.1002/slct.202400275

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Citations (1)

Tozasertib Attenuates Neuropathic Pain by Interfering with Aurora Kinase and KIF11 Mediated Nociception

ACS Chemical Neuroscience (2021)

Ankit Uniyal P. A. Shantanu Shivani Vaidya Daria A. Belinskaia Natalia N. Shestakova

Kinesins are the motor proteins that transport excitatory receptors to the synaptic membrane by forming a complex with receptor cargo leading to central sensitization causing neuropathic pain. Many regulatory proteins govern the transit of receptors by activating kinesin, and Aurora kinases are one of them. In this study, we have performed in silico molecular dynamics simulation to delineate the dynamic interaction of Aurora kinase A with its pharmacological inhibitor, tozasertib. The results from the molecular dynamics study shows that tozasertib-Aurora kinase A complex is stabilized through hydrogen bonding, polar interactions, and water bridges. Findings from the in vitro studies suggest that tozasertib treatment significantly attenuates lipopolysaccharide (LPS)-induced increase in oxidonitrosative stress and kif11 overexpression in C6 glial cell lines. Further, we investigated the regulation of kif11 and its modulation by tozasertib in an animal model of neuropathic pain. Two weeks post-CCI surgery we observed a significant increase in pain hypersensitivity and kif11 overexpression in DRG and spinal cord of nerve-injured rats. Tozasertib treatment significantly attenuates enhanced pain hypersensitivity along with the restoration of kif11 expression in DRG and spinal cord and oxidonitrosative stress in the sciatic nerve of injured rats. Our findings demonstrate the potential role of tozasertib for the management of neuropathic pain.

10.1021/acschemneuro.1c00043

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Citations (19)

N-alkylated thiazolidine-2,4-dione analogs as PTP1B inhibitors: synthesis, biological activity, and docking studies

Medicinal Chemistry Research (2017)

Manoj Kumar Mahapatra Rajnish Kumar Manoj Kumar

Docking (animal)

Thiazolidine

Moiety

10.1007/s00044-017-1823-z

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Citations (17)