Biology subjects

Sangeet, S.

Publications and source records attributed to Sangeet, S..

8 recordsLinked to original sources

bioRxiv2026

Quantitative Modelling of Amyloid-β Dynamics in Brain, CSF, and Plasma During Sleep and Wakefulness

Amyloid-beta (A{beta}) accumulation in the brain is linked to Alzheimer's disease. In healthy individuals, A{beta} rises during wakefulness and is cleared during sleep, yet the effects of sleep disturbances on the A{beta} dynamics are unclear. We developed a model, incorporating brain, cerebrospinal fluid (CSF), and plasma, to investigate the A{beta} dynamics along the sleep-wake cycles. The model reproduces the experimentally observed 24-hour A{beta}42 oscillations in CSF (660-760 pg/mL) and plasma (15-19 pg/mL) and predicts brain A{beta} dynamics. Indwelling lumbar catheter data show elevated CSF A{beta}42 levels on the second morning after a full night of sleep compared to first morning. The model predicts this increased level is due to repeated CSF sampling, which affects A{beta} levels through pressure-mediated changes in CSF, impaired sleep associated clearance, or their synergistic effect. These findings provide a framework for understanding A{beta} regulation, highlighting sleep's protective role and the need for non-invasive measurement approaches.

neuroscience↗

bioRxiv2024

EVOLVE: A Web Platform for Evolutionary Phase Analysis and New Variant Exploration from Multi-Sequence Data

Recurrent updates from the World Health Organization (WHO) on refining definitions for Variants of Concern (VOCs), Variants of Interest (VOIs), and Variants Under Monitoring (VUMs) underscore the need for systematic investigations to develop quantifiable metrics that differentiate critical phases of variant evolution. This study illustrates how protein data can be systematically analyzed by applying phase transition principles from statistical mechanics, where quantifying mutational response function (MRF) helps identify concerning variants along evolutionary paths. To support the exploration of metrics like mutational entropy, MRF, and other relevant indicators for novel or uncharacterized viruses and pathogenic bacteria, we introduce EVOLVE--a web platform that empowers researchers across diverse fields to access sequence-based analyses. EVOLVE streamlines data upload and analysis with a user-friendly interface and comprehensive tutorials. Overcoming the challenges with large sequence-space analysis its AI-driven data-learning module integrates evolutionary dynamics with microscopic mutational information, enabling the prediction of future site-specific mutations in prospective missense variants. Access EVOLVE for free at https://www.evolve-0fm3.onrender.com.

biophysics↗

bioRxiv2024

Machine Learning-Enhanced Drug Discovery for BACE1: A Novel Approach to Alzheimer's Therapeutics

Alzheimers disease (AD) remains a significant global health challenge, with BACE1, a critical therapeutic target due to its role in the amyloidogenic pathway. This study presents an innovative approach to drug development by integrating machine learning (ML) techniques to identify the potential BACE1 inhibitors. Utilizing a comprehensive dataset of protein-ligand interactions, the current study employed a machine learning model to generate novel ligands with high binding affinity and specificity for the BACE1 active site. The models efficacy was validated through molecular docking studies, which demonstrated superior binding affinities compared to existing FDA-approved inhibitors such as Atabecestat and Lanabecestat. The findings reveal that the top candidate, MLC10, exhibits a unique mechanism of action by promoting controlled flexibility in BACE1, contrasting with the rigid conformations induced by traditional inhibitors. This dynamic modulation enhances the enzymes inhibition, suggesting a promising avenue for therapeutic intervention. Furthermore, solvent-accessible surface area analyses indicate that MLC10 facilitates a more favourable protein conformation, potentially altering catalytic behaviour through increased solvent interactions. This work underscores the transformative potential of machine learning in drug discovery, paving the way for the development of next-generation BACE1 inhibitors. By harnessing computational techniques, the present work aims to address the limitations of current therapies and contribute to more effective treatments for Alzheimers disease, ultimately improving patient outcomes and quality of life.

bioinformatics↗

bioRxiv2024

Bacopa monnieri phytochemicals as promising BACE1 inhibitors for Alzheimers Disease Therapy

Alzheimers disease (AD) remains a formidable challenge, necessitating the discovery of effective therapeutic agents targeting {beta}-site amyloid precursor protein cleaving enzyme 1 (BACE1). This study investigates the inhibitory potential of phytochemicals derived from Bacopa monnieri, a plant renowned for its cognitive-enhancing properties, in comparison to established synthetic inhibitors such as Atabecestat, Lanabecestat, and Verubecestat. Utilizing molecular docking and advanced computational simulations, we demonstrate that Bacopaside I exhibits superior binding affinity and a unique interaction profile with BACE1, suggesting a more nuanced inhibitory mechanism. Our findings highlight the promising role of Bacopa monnieri phytochemicals as viable alternatives to synthetic drugs, emphasizing their potential to overcome limitations faced in clinical settings. Furthermore, the development of the SIMANA (https://simana.streamlit.app/) platform enhances the visualization and analysis of protein-ligand interactions, facilitating a deeper understanding of the dynamics involved. This research not only underscores the therapeutic promise of natural compounds in AD treatment but also advocates for a paradigm shift towards integrating traditional medicinal knowledge into contemporary drug discovery efforts.

bioinformatics↗

bioRxiv2023

An in-silico approach to identify bioactive phytochemicals from Houttuynia cordata Thunb. As potential inhibitors of Human Glutathione Reductase

Cellular infections underpin the pathogenesis of cancer and malaria. Mitigating cellular oxidative stress via glutathione reductase (GR) inhibition emerges as a promising therapeutic avenue. Exploiting the antioxidant-rich Houttuynia cordata Thunb., we investigated natural GR inhibitors. Among 13 docked phytochemicals, Quercetin, Quercitrin, and Sesamin exhibited exceptional GR binding affinities. Molecular Docking analysis highlighted their propensity to precisely target the GR active site. Subsequent 150 ns molecular dynamics simulations corroborated their robust interactions, unveiling dynamic stabilizing effects on the protein structure and bolstering their antioxidant potential. Furthermore, ADME-Tox profiling affirmed their favourable drug-like attributes. These findings underscore H. cordatas reservoir of potent antioxidants, poised to combat various maladies, including malaria and cancer. This study distinctly accentuates the distinctive outcomes and paramount significance of harnessing H. cordata phytochemicals as efficacious antioxidants, unravelling novel therapeutic avenues.

pharmacology and toxicology↗

bioRxiv2022

Small molecules from Bacopa monneiri as potent inhibitors against Neurodegenerative disorders

Alzheimers is characterized by the formation of senile plaques and fibril tangles. Several methodologies have been employed to treat the disease. Albeit engineered medications which are accessible for the treatment of Alzheimers, due to their numerous side-effects, it becomes imperative to formulate and synthesize novel drug candidates. Plants could be utilized as an alternative for these manufactured medications because of their low incidental effects in contrast with the engineered drugs. Bacopa monneiri (BM) is a therapeutic plant which is accounted for to be utilized to treat NDs. Therefore, in current study an in-silico approach was carried out to evaluate the pharmacological effect of BM. Molecular Docking was carried out to screen the active phytochemicals of BM which can act as potential drug candidates against amyloid-{beta} plaques. A total of 8 biologically active phytochemicals from BM were docked against p75NTR receptor. Based on molecular docking study it was observed that the phytocompounds Bacopasaponin D and Bacopasaponin G of BM significantly fits to the active site of p75NTR. Further Molecular Dynamics simulation study was performed to examine the stability of the binding of these phytochemicals with the selected targets. Our findings suggested that the phytocompounds Bacopasaponin D and Bacopasaponin G significantly binds with p75NTR and thus might have a potential to inhibit the natural binding activity of amyloid-b plaques and act as a potential anti-neurodegenerative drug.

bioinformatics↗

bioRxiv2022

In silico analysis of Bacopa monnieri (L.) Wettst. compounds for drug development against Neurodegenerative Disorders

Neurotrophins play a crucial role in the development and regulation of neurons. Alterations in the functioning of these Neurotrophins leads to several Neurodegenerative Disorders. Albeit engineered medications which are accessible for the treatment of Neurodegenerative Disorders, due to their numerous side-effects, it becomes imperative to formulate and synthesize novel drug candidates. Plants could be utilized as an alternative for these manufactured medications because of their low incidental effects in contrast with the engineered drugs. Bacopa monnieri has been traditionally known to be utilized to treat Neurodegenerative Disorders. Therefore, in current study an in-silico based study was carried out to evaluate the pharmacological effect of Bacopa monnieri. Molecular Docking was carried out to screen the active phytochemicals of Bacopa monnieri which can act as potential drug candidates against the causative proteins of Neurodegenerative Disorders. A total of 105 biologically active phytochemicals from Bacopa monnieri were docked against the receptors of brain-derived neurotrophic factor, neurotrophin-3, neurotrophin-4, and nerve growth factor. Based on molecular docking study it was observed that the phytocompounds Vitamin E, Benzene propanoic acid, 3,5-bis(1,1dimethylethyl)4-hydroxy-, methyl ester (BPA), Stigmasterol, and Nonacosane of Bacopa monnieri significantly fits to the active residues of the four selected drug targets. Further Molecular Dynamics simulation study was performed to examine the stability of the binding of these phytochemicals with the selected targets. Drug likeness properties as well as related physico-chemical properties were analyzed through ADMETox study. Our findings suggested that the phytocompounds Vitamin E, BPA, Stigmasterol and Nonacosane significantly bind against brain-derived neurotrophic factor, neurotrophin-3, neurotrophin4, and nerve growth factor, respectively which may be the potential drug candidates for the treatment of neurodegenerative disorders. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/486025v1_ufig1.gif" ALT="Figure 1"> View larger version (55K): org.highwire.dtl.DTLVardef@2c39aforg.highwire.dtl.DTLVardef@17f4fd9org.highwire.dtl.DTLVardef@1534e13org.highwire.dtl.DTLVardef@2ad383_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2021

In-silico studies of Neurocognitive and Neuropharmacological effect of Bacopa monnieri (L.)

Different Indian therapeutic plants have picked up consideration for their restorative properties against neurodevelopmental disorders lately. Bacopa monnieri (B. monnieri), being one of them, finds its utilization significantly in the treatment of cognition and learning. Despite the fact that it possesses such great capacity to treat neurological issues, how precisely it confers its influence is muddled. This study makes a stride towards knowing which phytochemical is significantly associated with granting B. monnieri with therapeutic properties. The docking investigation and the molecular simulation studies proposes that there is no single phytochemical included that imparts B. monnieri a significant medicinal effect. It is really the blend of dominant part of natural phytochemicals present in B. monnieri that bestows the anti-neurological activity to B. monnieri. The ADME studies shows the convergence of properties of phytochemicals of B. monnieri with that of commercially available drugs which suggests that phytochemicals of B. monnieri can used as a potential drug source to treat neurodegenerative and neurodevelopmental disorders.

pharmacology and toxicology↗