NEUROPROTECTIVE ROLE OF BIMOCLOMOL IN ECTOPIC CELL CYCLE IN PARKINSON'S DISEASE: NEW INSIGHTS

Objective: Parkinson's disease (PD) is a debilitating age-related neurodegenerative disease characterized by the canonical formation of intracellular Lewy bodies comprising α-synuclein protein. Despite the knowledge of factors causing PD, it remains irreversible and incurable. Recent studies have highlighted the physiological and pathological involvement of cell cycle proteins in PD. The intriguing relationship between PARK2 and cyclin E which leads to upregulation of cyclin E in the absence of functional PARK2 contributes heavily in the onset and progression of PD. The objective of this study is to explore neuroprotective action of bimoclomol in attenuating the level of cyclin E and inhibiting post-mitotic cell division led neurodegeneration in PD. Methods: We employed various in silico methods such as drug-likeness parameters, namely, Lipinski filter analysis, Ghose parameters, Veber rules, absorption, distribution, metabolism, and excretion - toxicity analysis, pharmacophore based target prediction, active site prediction, and molecular docking studies. Results: The binding of bimoclomol inhibited cyclin E, thereby, attenuating post-mitotic cell division led neurodegeneration in PD. Conclusion: This study outlines the novel potential of bimoclomol in attenuating cyclin E led neuronal death in PD which may be mediated by heat shock proteins (HSP70)

BIOMOLECULES MEDIATED TARGETING OF VASCULAR ENDOTHELIAL GROWTH FACTOR IN NEURONAL DYSFUNCTION: AN IN SILICO APPROACH

Objective: Neurodegenerative diseases are a debilitating age-related disorder manifested by memory loss, impaired motor activity, and loss of muscle tone due to the accumulation of toxic metabolites in the brain. Despite the knowledge of factors causing neurodegenerative disorders, it remains irreversible and incurable. Growing evidence have currently advocated the physiological and pathological contribution of hypoxia-induced vascular endothelial growth factor (VEGF) in neuronal loss. The objective of this research report highlights biomolecules mediated targeting of VEGF activity based on in silico approaches that could establish a potential therapeutic window for the treatment of different abnormalities associated with impaired VEGF.Methods: We employed various in silico methods such as drug-likeness parameters, namely, Lipinski filter analysis, Pock Drug tool for active site prediction, AUTODOCK 4.2.1, and LigPlot1.4.5 for molecular docking studiesResults: Three-dimensional structure of VEGF was generated and Ramachandran plot obtained for quality assessment. RAMPAGE displayed 99.5% of residues in the most favored regions, 0.5% residues in additionally allowed, and no residues in disallowed regions in VEGF, showing that stereochemical quality of protein structure is good. Further, initial screenings of the molecules were done based on Lipinski's rule of five. Finally, we have found Naringenin to be most effective among three biomolecules in modulating VEGF activity based on minimum inhibition constant, Ki, and highest negative free energy of binding with the maximum interacting surface area during docking studies.Conclusion: The present study outlines the novel potential of biomolecules in regulating VEGF activity for the treatment of different abnormalities associated with impaired VEGF

AN IN SILICO STUDY OF NARINGENIN-MEDIATED NEUROPROTECTION IN PARKINSON'S DISEASE

  Objective: Naringenin is a dietary biomolecule with broad spectrum of activities which protects neurons from various neurotoxic insults and improves cognition and motor function in neurodegenerative diseases. DJ-1 has both, ubiquitin E3 ligase as well as chaperonic activity, and loss of ubiquitin E3 ligase activity of DJ-1 has been found to be associated with familial Parkinson's disease (PD). Naringenin induced E3 ligase activity of DJ-1 which can have possible clinical relevance in PD.Methods: Various in silico parameters such as phylogenetic analysis, homology modeling, active site prediction, and molecular docking studies using AutoDock 4.2.1 and LIGPLOT1.4.5 were carried out.Results: Three-dimensional structure of DJ-1 was generated and Ramachandran plot was obtained for quality assessment. RAMPAGE displayed 99.5% of residues in the most favored regions. 0% residues in additionally allowed and 0.5% disallowed regions of DJ-1 protein. Further, initial screenings of the molecules were done based on Lipinski's rule of five. CastP server used to predict the ligand binding site suggests that this protein can be utilized as a potential drug target. Finally, we have found naringenin to be most effective among four biomolecules in modulating DJ-1 based on minimum inhibition constant, Ki, and highest negative free energy of binding with maximum interacting surface area in the course of docking studies.Conclusion: Our study suggests that based on different in silico parameters and molecular docking studies, naringenin can provide a new avenue for PD therapeutics

MOLECULAR DOCKING STUDY OF NEUROPROTECTIVE PLANT-DERIVED BIOMOLECULES IN PARKINSON'S DISEASE

Objective: The objective of this study was to explore the therapeutic role of biomolecules in targeting the altered expression of Parkin in PD pathogenesis.Methods: We employed various in silico tools such as drug-likeness parameters, namely, Lipinski filter analysis, Muscle tool for phylogenetic analysis, Castp Server for active site prediction, molecular docking studies using AutoDock 4.2.1 and LIGPLOT1.4.5 were carried out.Results: Our results show that neuroprotective activity of Quercetin to be most effective and can provide their possible clinical relevance in PD. Further, initial screenings of the molecules were done based on Lipinski's rule of five. CastP server used to predict the ligand binding site suggests that this protein can be utilized as a potential drug target. Finally, we have found Quercetin to be most effective amongst four biomolecules in modulating Parkin based on minimum inhibition constant, Ki and highest negative free energy of binding with the maximum interacting surface area in a course of docking studies.Conclusion: This research could provide a potential therapeutic window for the treatment of PD

MOLECULAR DOCKING STUDIES FOR THE COMPARATIVE ANALYSIS OF DIFFERENT BIOMOLECULES TO TARGET HYPOXIA INDUCIBLE FACTOR-1α

Objective: Hypoxia plays a significant role in governing many vital signalling molecules in the central nervous system (CNS). Hypoxic exposure has also been depicted as a stimulus for oxidative stress, increase in lipid peroxidation, DNA damage, blood-brain dysfunction, impaired calcium (Ca2+) homoeostasis and agglomeration of oxidized biomolecules in neurons, which act as a novel signature in diverse neurodegenerative and oncogenic processes. On the contrary, the presence of abnormally impaired expression of HIF-1α under hypoxic insult could serve as an indication of the existence of tumors and neuronal dysfunction as well. For instance, under hypoxic stress, amyloid-β protein precursor (AβPP) cleavage is triggered due to the higher expression of HIF-1α and thus leads to synaptic loss. The objective of this research is to perform comparative studies of biomolecules in regulating HIF-1α activity based on in silico approaches that could establish a potential therapeutic window for the treatment of different abnormalities associated with impaired HIF-1α.Methods: We employed various in silico methods such as drug-likeness parameters namely Lipinski filter analysis, Muscle tool, SWISS-MODEL, active site prediction, Auto Dock 4.2.1 and LigPlot1.4.5for molecular docking studies.Results: 3D structure of HIF-1α was generated and Ramachandran plot obtained for quality assessment. RAMPAGE displayed 99.5% of residues in the most favoured regions. 0% residues in additionally allowed and 0.5% disallowed regions of the HIF-1α protein. Further, initial screenings of the molecules were done based on Lipinski's rule of five. Cast P server used to predict the ligand binding site suggests that this protein can be utilised as a potential drug target. Finally, we have found Naringenin to be most effective amongst three biomolecules in modulating HIF-1α based on minimum inhibition constant, Ki and highest negative free energy of binding with the maximum interacting surface area during docking studies.Conclusion: The present study outlines the novel potential of Biomolecules in regulating HIF-1α activity for the treatment of different abnormalities associated with impaired HIF-1α

Detecting Fast Radio Bursts with Spectral Structure using the Continuous Forward Algorithm

Detecting fast radio bursts (FRBs) with frequency-dependent intensity remains a challenge, as existing search algorithms do not account for the spectral shape, potentially leading to non-detections. We propose a novel detection statistic, which we call the Kalman detector, that improves the sensitivity of FRB signal detection by incorporating spectral shape information. The detection statistic is based on an optimal matched filter, marginalizing over all possible intensity functions, weighted by a random walk probability distribution, considering some decorrelation bandwidth. Our analysis of previously detected FRBs demonstrates that the Kalman score provides a comparable yet independent source of information for bursts with significant spectral structure, and the sensitivity improvement is of the order 0%--200% with a median improvement of 20%. We also applied the Kalman detector to existing data from FRB 20201124A and detected two new repeat bursts that were previously missed. Furthermore, we suggest a practical implementation for real-time surveys by employing a low significance soft-trigger from initial flux integration-based detection algorithms. The Kalman detector has the potential to significantly enhance FRB detection capabilities and enable new insights into the spectral properties of these enigmatic astrophysical phenomena.Comment: 16 pages, 8 figures; accepted for publication in Ap

Spectropolarimetric variability in the repeating fast radio burst source FRB 20180301A

As the sample size of repeating fast radio bursts (FRBs) has grown, an increasing diversity of phenomenology has emerged. Through long-term multi-epoch studies of repeating FRBs, it is possible to assess which phenomena are common to the population and which are unique to individual sources. We present a multi-epoch monitoring campaign of the repeating FRB source 20180301A using the ultra-wideband low (UWL) receiver observations with Murriyang, the Parkes 64-m radio telescope. The observations covered a wide frequency band spanning approximately 0.7--4 GHz, and yielded the detection of 46 bursts. None of the repeat bursts displayed radio emission in the range of 1.8--4 GHz, while the burst emission peaked at 1.1 GHz. We discover evidence for secular trends in the burst dispersion measure, indicating a decline at a rate of $-2.7\pm0.2\,{\rm pc\,cm^{-3}\,yr^{-1}}$. We also found significant variation in the Faraday rotation measure of the bursts across the follow-up period, including evidence of a sign reversal. While a majority of bursts did not exhibit any polarization, those that did show a decrease in the linear polarization fraction as a function of frequency, consistent with spectral depolarization due to scattering, as observed in other repeating FRB sources. Surprisingly, no significant variation in the polarization position angles was found, which is in contrast with earlier measurements reported for the FRB source. We measure the burst rate and sub-pulse drift rate variation and compare them with the previous results. These novel observations, along with the extreme polarization properties observed in other repeating FRBs, suggest that a sub-sample of FRB progenitors possess highly dynamic magneto-ionic environments.Comment: 21 pages, 14 figures; accepted for publication in MNRA