Phytoconstituents Targeting the Serotonin 5-HT3 Receptor: Promising Therapeutic Strategies for Neurological Disorders.

The 5-hydroxytryptamine-3 receptor (5-HT3R), a subtype of serotonin receptor, is a ligand-gated ion channel crucial in mediating fast synaptic transmission in the central and peripheral nervous systems. This receptor significantly influences various neurological activities, encompassing neurotransmission, mood regulation, and cognitive processing; hence, it may serve as an innovative target for neurological disorders. Multiple studies have revealed promising results regarding the beneficial effects of these phytoconstituents and extracts on conditions such as nausea, vomiting, neuropathic pain depression, anxiety, Alzheimer's disease, cognition, epilepsy, sleep, and dyskinesia via modulation of 5-HT3R in the pathophysiology of neurological disorder. The review delves into a detailed exploration of in silico, in vitro, and in vivo studies and clinical studies that discussed phytoconstituents acting on 5-HT3R and attenuates difficulties in neurological diseases. The diverse mechanisms by which plant-derived phytoconstituents influence 5-HT3R activity offer exciting avenues for developing innovative therapeutic interventions. Besides producing an agonistic or antagonistic effect, some phytoconstituents exert modulatory effects on 5-HT3R activity through multifaceted mechanisms. These include γ-aminobutyric acid and cholinergic neuronal pathways, interactions with neurokinin (NK)-1, NK2, serotonergic, and γ-aminobutyric acid(GABA)ergic systems, dopaminergic influences, and mediation of calcium ions release and inflammatory cascades. Notably, the phytoconstituent's capacity to reduce oxidative stress has also emerged as a significant factor contributing to their modulatory role. Despite the promising implications, there is currently a dearth of exploration needed to understand the effect of phytochemicals on the 5-HT3R. Comprehensive preclinical and clinical research is of the utmost importance to broaden our knowledge of the potential therapeutic benefits associated with these substances.

Machine learning-based virtual screening and molecular modelling studies for identification of butyrylcholinesterase inhibitors as anti-Alzheimer's agent.

Butyrylcholinesterase (BChE) is a hydrolase involved in the metabolism and detoxification of specific esters in the blood. It is also implicated in the progression of Alzheimer's disease, a type of dementia. As the disease progresses, the level of BChE tends to increase, opting for a major role as an acetylcholine-degrading enzyme and surpassing the role of acetylcholinesterase. Hence, the development of BChE inhibitors could be beneficial for the latter stages of the disease. In the present study, machine learning (ML) models were developed and employed to identify new BChE inhibitors. Further, the identified molecules were subjected to molecular property filters. The filtered ligands were studied through molecular modelling techniques, viz. molecular docking and molecular dynamics (MD). Support vector machine-based ML models resulted in the identification of 3291 compounds that would have predicted IC50 values less than 200 nM. The docking study showed that compounds ART13069594, ART17350769 and LEG19710163 have mean binding energies of -9.62, -9.26 and -8.93 kcal/mol, respectively. The MD study displayed that all the selected ligands showed stable complexes with BChE. The trajectories of all the ligands were stable similar to the standard BChE inhibitors.Communicated by Ramaswamy H. Sarma.

Centella asiatica improves memory and executive function in middle-aged rats by controlling oxidative stress and cholinergic transmission.

ETHNOPHARMACOLOGICAL RELEVANCE: Centella asiatica (L.) Urban, is a medicinal herb with rich history of traditional use in Indian subcontinent. This herb has been valued for its diverse range of medicinal properties including memory booster, and also as a folk treatment for skin diseases, wound healing and mild diuretic. AIM OF STUDY: Aging is a gradual and continuous process of natural decay in the biological systems, including the brain. This work aims to evaluate the effectiveness of ethanolic extract of Centella asiatica (CAE) on age-associated cognitive impairments in rats, as well as the underlying mechanism. MATERIAL AND METHODS: Rats were allocated into five distinct groups of 5 animals each: Young rats (3 months old rats), middle-aged (m-aged) rats (13-14 months old), and the remaining three groups were comprised of m-aged rats treated with different concentrations of CAE, viz., 150, 300, and 450 mg/kg b. w., orally for 42 days. Y-maze, open field, novel object recognition, and elevated plus maze tests were used to assess animal behavior. The malondialdehyde (MDA), superoxide dismutase (SOD), and acetylcholinesterase (AChE) assays; and H&E staining were done in the rat brain to assess the biochemical and structural changes. CAE was also subjected to HPLC analysis, in vitro antioxidant and anti-cholinergic activity. The active compounds of CAE were docked with AChE and BuChE in molecular docking study. RESULTS: The results showed that CAE treatment improves behavioral performance; attenuates the age-associated increase in MDA content, SOD, and AChE activity; and reduces neuronal loss. In vitro study showed that CAE has concentration-dependent antioxidant and anti-AChE activity. Furthermore, the presence of Asiatic acid and Madecassic acid in CAE and their good binding with cholinergic enzymes (in silico) also suggest the anticholinergic effect of CAE. CONCLUSION: The findings of the current study show that the anticholinergic and antioxidant effects of CAE are attributable to the presence of Asiatic acid and Madecassic acid, which not only provide neuroprotection against age-associated cognitive decline but also reverse it.

Preparation, Characterization, in-vitro and in-vivo Pharmacokinetic Evaluation of Thermostable Dimethyl Fumarate Cocrystals.

Dimethyl fumarate (DMF) is an FDA-approved drug for treating relapsing-remitting multiple sclerosis; but it is susceptible to sublimation leading to its loss during processing. Cocrystals can protect against thermal energy via the interaction of DMF with a coformer via weak forces of interaction. With this hypothesis, we have, for the first time, prepared DMF cocrystals using the solvent evaporation method using coformers like citric acid and succinic acid screened by in-silico predictions and hydrogen bonding properties. Analysis using infra-red (IR), powder x-ray diffraction (PXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and sublimation evaluation characterized cocrystals and their thermostability. Comparative analysis of the release profile has been done by dissolution and pharmacokinetic study of DMF and its cocrystals. The cocrystals have improved thermal stability and better pharmacological activities than DMF. In the safety and efficacy evaluation of the formulated cocrystals, they were found to be non-cytotoxic, antioxidant, and inhibiting IL-6 and TNF-α in PBMC induced by lipopolysaccharide (LPS). We have obtained cocrystals of DMF with improved thermal stability and better pharmacological activities than DMF.

Effect of sulfonamide derivatives of phenylglycine on scopolamine-induced amnesia in rats.

Alzheimer's disease is a neurodegenerative disease responsible for dementia and other neuropsychiatric symptoms. In the present study, compounds 30 and 33, developed earlier in our laboratory as selective butyrylcholinesterase inhibitors, were tested against scopolamine-induced amnesia to evaluate their pharmacodynamic effect. The efficacy of the compounds was determined by behavioral experiments using the Y-maze and the Barnes maze and neurochemical testing. Both compounds reduced the effect of scopolamine treatment in the behavioral tasks at a dose of 20 mg/kg. The results of the neurochemical experiment indicated a reduction in cholinesterase activity in the prefrontal cortex and the hippocampus. The levels of antioxidant enzymes superoxide dismutase and catalase were restored compared to the scopolamine-treated groups. The docking study on rat butyrylcholinesterase (BChE) indicated tight binding, with free energies of -9.66 and -10.23 kcal/mol for compounds 30 and 33, respectively. The two aromatic amide derivatives of 2-phenyl-2-(phenylsulfonamido) acetic acid produced stable complexes with rat BChE in the molecular dynamics investigation.

Small size silver nanoparticles loaded with glycoside rich portion of Boerhavia Diffusa Linn. promotes wound healing: in-silico and in-vivo studies.

Silver nanoparticles (Ag-NPs) are increasingly used in various fields, including medicine, owing to their unique physicochemical properties. Due to their smaller size, the contact with biological components is increased, and consequently, it performs better as an antibacterial and antimicrobial. In this study, the authors have focused on the synthesis of small-sized spherical silver nanoparticles (Ag-NPs) by a chemical reduction method using two different capping agents and concentrations of AgNO3 as a precursor. Additionally, various amounts of Glycoside Rich Portion (GRP) isolated from the roots of Boerhaavia diffusa L. were loaded onto synthesised Ag-NPs. Punarnavoside, a glycoside found in GRP, has been reported to have antifibrinolytic properties. The docking study of punarnavoside present in GRP has shown good binding affinity with various antifibrinolytic targets. The surface plasmon resonance band, particle size, polydispersity index, and zeta potential values have been used to analyse the interaction and kind of bonding between GRP and Ag-NPs. A batch of trisodium citrate (TSC)-capped Ag-NPs loaded with 0.1 ml of 1% GRP solution showed particle size smaller than 50 nm with a stable zeta potential value of - 55.3 mV. Fourier transform infrared spectroscopic results showed CO and C-O bonds in GRP interacted with Ag-NPs. A batch of TSC-capped GRP-loaded Ag-NPs (1%)-based gel was developed using carbopol as a polymer. The TSC-capped GRP-loaded silver nanogel had greater wound closure in rats, as observed during the histopathological studies in the excision wound model. The antifibrinolytic activity of GRP, when coupled with the antibacterial and bactericidal properties of silver, demonstrated an increased wound healing effect.

Discovery of triazole-bridged aryl adamantane analogs as an intriguing class of multifunctional agents for treatment of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive brain disorder associated with slow loss of brain functions leading to memory failure and modest changes in behavior. The multifactorial neuropathological condition is due to a depletion of cholinergic neurons and accumulation of amyloid-beta (Aß) plaques. Recently, a multi-target-directed ligand (MTDL) strategy has emerged as a robust drug discovery tool to overcome current challenges. In this research work, we aimed to design and develop a library of triazole-bridged aryl adamantane analogs for the treatment of AD. All synthesized analogs were characterized and evaluated through various in vitro and in vivo biological studies. The optimal compounds 32 and 33 exhibited potent inhibitory activities against acetylcholinesterase (AChE) (32 - IC50 = 0.086 µM; 33 - 0.135 µM), and significant Aß aggregation inhibition (20 µM). N-methyl-d-aspartate (NMDA) receptor (GluN1-1b/GluN2B subunit combination) antagonistic activity of compounds 32 and 33 measured upon heterologous expression in Xenopus laevis oocytes showed IC50 values of 3.00 µM and 2.86 µM, respectively. The compounds possessed good blood-brain barrier permeability in the PAMPA assay and were safe for SH-SY5Y neuroblastoma (10 µM) and HEK-293 cell lines (30 µM). Furthermore, in vivo behavioral studies in rats demonstrated that both compounds improved cognitive and spatial memory impairment at a dose of 10 mg/kg oral administration. Together, our findings suggest triazole-bridged aryl adamantane as a promising new scaffold for the development of anti-Alzheimer's drugs.

Novel Gastroprotective and Thermostable Cocrystal of Dimethyl Fumarate: Its Preparation, Characterization, and In Vitro and In Vivo Evaluation.

Crystallization has revolutionized the field of solid-state formulations by modulating the physiochemical and release profile of active pharmaceutical ingredients (APIs). Dimethyl fumarate (DF), an FDA-approved first-line drug for relapsing-remitting multiple sclerosis, has a sublimation problem, leading to loss of the drug during its processing. To tackle this problem, DF cocrystal has been prepared by using solvent evaporation technique using nicotinamide as a coformer, which has been chosen based on in silico predictions and their ability to participate in hydrogen bonding. Fourier transform infrared (FT-IR), powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), and sublimation analysis have characterized the cocrystal and its thermostability. Comparative analysis of the release profile has been done by the dissolution and pharmacokinetic study of DF and its cocrystal. Formulated cocrystal is noncytotoxic, antioxidant and inhibits interleukin-6 and tissue necrosis factor-α in peripheral blood mononuclear cells induced by lipopolysaccharide. We have obtained a thermostable cocrystal of DF with a similar physicochemical and release profile to that of DF. The formulated cocrystal also provides a gastroprotective effect which helps counterbalance the adverse effects of DF by reducing lipid peroxidation and total nitrite levels.

An Overview of Chemistry, Kinetics, Toxicity and Therapeutic Potential of Boldine in Neurological Disorders.

Boldine is an alkaloid obtained from the medicinal herb Peumus boldus (Mol.) (Chilean boldo tree; boldo) and belongs to the family Monimiaceae. It exhibits a wide range of pharmacological effects such as antioxidant, anticancer, hepatoprotective, neuroprotective, and anti-diabetic properties. There is a dearth of information regarding its pharmacokinetics and toxicity in addition to its potential pharmacological activity. Boldine belongs to the aporphine alkaloid class and possesses lipophilic properties which enable its efficient absorption and distribution throughout the body, including the central nervous system. It exhibits potent free radical scavenging activity, thereby reducing oxidative stress and preventing neuronal damage. Through a variety of neuroprotective mechanisms, including suppression of AChE and BuChE activity, blocking of connexin-43 hemichannels, pannexin 1 channel, reduction of NF-κß mediated interleukin release, and glutamate excitotoxicity which successfully reduces neuronal damage. These results point to its probable application in reducing neuroinflammation and oxidative stress in epilepsy, Alzheimer's disease (AD), and Parkinson's disease (PD). Moreover, its effects on serotonergic, dopaminergic, opioid, and cholinergic receptors were further investigated in order to determine its applicability for neurobehavioral dysfunctions. The article investigates the pharmacokinetics of boldine and reveals that it has a low oral bioavailability and a short half-life, requiring regular dosage to maintain therapeutic levels. The review studies boldine's potential therapeutic uses and mode of action while summarizing its neuroprotective benefits.  Given the favorable results for boldine as a potential neurotherapeutic drug in laboratory animals, more research is required. However, in order to optimise its therapeutic potential, it must be more bioavailable with fewer detrimental side effects.

Pharmacophore-based virtual screening, molecular docking and molecular dynamics simulations study for the identification of LIM kinase-1 inhibitors.

LIM kinases (LIMKs) are a family of protein kinases involved in the regulation of actin dynamics. There are two isoforms of LIMKs i.e., LIMK1 and LIMK2. LIMK1 is expressed abundantly in neuronal tissues. LIMK1 plays an essential role in the degradation of dendritic spines, which are important for our higher brain functions, such as memory and learning. The inhibition of LIMK1 improves the size and density of dendritic spines and acts as a protective effect against Alzheimer's disease. In this study, we have adopted ligand-based drug design and molecular modelling methods to identify virtual hits. The pharmacophoric features of PF-00477736 were used to screen the Zinc15 compounds library. The identified hits were then passed through drug-likeliness and PAINS filters. Further, comprehensive docking and rigorous molecular dynamics simulation study afforded three virtual hits viz., ZINC504485634, ZINC16940431 and ZINC1091071. The hits showed a better docking score than the standard ligand, PF-00477736. The docking score was found to be -8.85, -7.50 and -7.68 kcal/mol. These hits exhibited optimal binding properties with the target in docking study, blood-brain barrier permeability, in silico pharmacokinetics and low predicted toxicity.Communicated by Ramaswamy H. Sarma.

Identification of potential death-associated protein kinase-1 (DAPK1) inhibitors by an integrated ligand-based and structure-based computational drug design approach.

Death-associated protein kinase 1 (DAPK1) is a calcium/calmodulin (Ca2+/CaM)-dependent serine/threonine kinase that is abundantly expressed in the memory- and cognition-related brain areas. DAPK1 is associated with several pathological hallmarks of Alzheimer's disease (AD); it is an attractive target for designing a novel DAPK1 inhibitor as an effective therapeutic treatment for AD. In the present study, we have used an integrated ligand-based and structure-based drug design method to identify DAPK1 inhibitors. The pharmacophoric features of compound 38 G (PDB ID 4TXC) were mapped, and the models were evaluated using enrichment factor (EF) and goodness of hit (GH) score. The selected models were used to screen Zinc 15 compounds library. The identified hits were passed through drug-likeliness and PAINS filtering. The docking study was performed in three steps to yield molecules with good binding energy and ligand-target interactions. Finally, three hits were obtained, that is, ZINC000020648330, ZINC000006755051 and ZINC000020650468, which were subjected to rigorous molecular dynamics simulation. All three hits exhibited optimal stability under simulated conditions and low predicted toxicity.Communicated by Ramaswamy H. Sarma.

Identification of novel glucocerebrosidase chaperone for potential treatment of Parkinson's disease: An approach using in silico virtual screening, molecular docking and molecular dynamics, and in vitro studies.

Glucocerebrosidase (GCase), a GBA1 gene-encoded lysosomal enzyme, is a risk factor for Parkinson's disease (PD). Chaperones that increase GCase activity can potentially be disease-modifying agents in PD. To date, none of the registered treatments has demonstrated disease-modifying effects. Thus, chaperones for GCase were identified using in-silico virtual screening, molecular property filtering, and molecular dynamics and validated by circular dichroism, FT-IR, and Raman spectroscopies. In-vitro enzyme kinetics, thermal denaturation assay (TDA), and cell-line model were used to test their potential for GCase In-silico investigation revealed four compounds as candidate chaperones with adequate brain penetrability and binding energy (BE). Of them, GC466 showed ideal chaperoning characteristics, including potent BE -8.92 ± 0.68 Kcal/mol and binding affinity (Ki) 0.64 ± 0.12 µM against rGCase (Asp146, Phe265, and His329 residues) at pH 7.0 than at 4.5 (BE: -5.06 Kcal/mol, Ki: not found). Spectroscopic results confirmed the stability of GCase by GC466. TDA determined its chaperoning behavior, signified by improved rGCase thermal stabilization with stabilization ratio of 10.20 at 10 µM. In addition, it demonstrated GCase restorative, neurorestorative, and ROS scavenging activity in 6-OHDA treated cell-line model. Therefore, the present study may offer a novel chaperone with the potential to be a disease-modifying agent for PD.

Combined ligand-based and structure-based design of PDE 9A inhibitors against Alzheimer's disease.

PDE9 enzyme hydrolyzes cGMP, which is involved in the regulation of synaptic plasticity through the NMDA pathway (a well-known excitotoxic target for AD) via activation of calcium/calmodulin-dependent neuronal NO synthases in the postsynaptic neurons. The inhibition of PDE9 leads to elevated cGMP levels, causing enhanced NMDA signaling and thus contributing to an increase in synaptic plasticity and stabilization. Therefore, it could be considered a pertinent target for AD drug discovery. PF-04447943 and BI-409306 targeting PDE9 are undergoing clinical trials (Phase II). The present study encompasses a pharmacophoric approach to identify potent PDE9 inhibitors using various computational methods. Pharmacophores generated from the PDB 6A3N yielded 37,554 virtual hits, which underwent drug likeliness and PAINS filtering to arrive at a few virtual leads. The leads were further subjected to extra precision docking, ADMET predictions, and molecular dynamics. The final hits, ZINC000001305675 and ZINC000000377099, showed superior docking scores of - 10.90 and - 10.30 kcal/mol and satisfactory predicted ADMET scores. The hits were subjected to molecular dynamics (MD) studies, wherein they formed stable complexes with PDE9 protein and had ligand RMSDs within acceptable limits. The processes involved in the combined ligand and structure-based strategies.

Identification of sulfonamide-based butyrylcholinesterase inhibitors using machine learning.

Aim: This study reports the designing of BChE inhibitors through machine learning (ML), followed by in silico and in vitro evaluations. Methodology: ML technique was used to predict the virtual hit, and its derivatives were synthesized and characterized. The compounds were evaluated by using various in vitro tests and in silico methods. Results: The gradient boosting classifier predicted N-phenyl-4-(phenylsulfonamido) benzamide as an active BChE inhibitor. The derivatives of the inhibitor, i.e., compounds 34, 37 and 54 were potent BChE inhibitors and displayed blood-brain barrier permeability with no significant AChE inhibition. Conclusion: The ML prediction was effective, and the synthesized compounds showed the BChE inhibitory activity, which was also supported by the in silico studies.

Generation of wild-type rat Glucocerebrosidase homology modeling: Identification of putative interactions site and mechanism for chaperone using combined in-silico and in-vitro studies.

Disease-modifying treatment strategy for Parkinson's disease (PD) by stabilization of Glucocerebrosidase (GCase) enzyme by chaperones is of particular interest. Wild-type rat is a widely used animal model for PD; however, the in-silico model to elucidate the nature of rat GCase (rGCase)-chaperone interactions, mechanisms, and structural stability is still unavailable. Hence, we have developed pH-dependent rGCase homology models, in-silico (docking and molecular dynamics), and in-vitro techniques (enzyme kinetics and thermal stability) to address this gap. The homology modeling results revealed ≥ 90% rGCase residues were in the favored regions, representing adequate models quality. In-silico studies showed an interaction between chaperone (Ambroxol, AMB) and the active site residues TYR 331, TYR 263, GLN 266, and GLU 358 with the higher affinity at neutral pH than acidic pH. In-vitro studies showed higher inhibitory activity (IC50) and binding affinity (Ki) of AMB at neutral pH (IC50: 8.2 ± 2.6 µM and Ki: 4.3 ± 1.2 µM) than acidic pH (IC50 and Ki: not identified). AMB improved rGCase thermostability was confirmed by thermal denaturation assay. We have developed the homology model for rGCase, which provides a perspective for designing and screening the chaperones at the initial phases of drug discovery to ameliorate PD.

Cathepsin B-A Neuronal Death Mediator in Alzheimer's Disease Leading to Neurodegeneration.

The lysosomal cysteine protease enzyme, named Cathepsin B, mainly degrades the protein and manages its average turnover in our body. The Cathepsin B active form is mostly present inside the lysosomal part at a cellular level, providing the slightly acidic medium for its activation. Multiple findings on Cathepsin B reveal its involvement in neurons' degeneration and a possible role as a neuronal death mediator in several neurodegenerative diseases. In this review article, we highlight the participation of Cathepsin B in the etiology/progress of AD, along with various other factors. The enzyme is involved in producing neurotoxic Aß amyloid in the AD brain by acting as the ß-secretase enzyme in the regulated secretory pathways responsible for APP processing. Aß amyloid accumulation and amyloid plaque formation lead to neuronal degeneration, one of the prominent pathological hallmarks of AD. Cathepsin B is also involved in the production of PGlu-Aß, which is a truncated and highly neurotoxic form of Aß. Some of the findings also revealed that Cathepsin B specific gene deletion decreases the level of PGlu-Aß inside the brain of experimental mice. Therefore, neurotoxicity might be considered a new pathological indication of AD due to the involvement of Cathepsin B. It also damages neurons present in the CNS region by producing inflammatory responses and generating mitochondrial ROS. However, Cathepsin B inhibitors, i.e., CA-074, can prevent neuronal death in AD patients. The other natural inhibitors are also equally effective against neuronal damage with higher selectivity. Its synthetic inhibitors are specific for their target; however, they lose their selectivity in the presence of quite a few reducing agents. Therefore, a humanized monoclonal antibody is used as a selective Cathepsin B inhibitor to overcome the problem experienced. The use of Cathepsin B for the treatment of AD and other neurodegenerative diseases could be considered a rational therapeutic target.

Identification of sulfonamide based butyrylcholinesterase inhibitors through scaffold hopping approach.

Butyrylcholinesterase (BChE), a hydrolytic enzyme, is responsible for the termination of the action of acetylcholine besides acetylcholinesterase (AChE) in the synaptic cleft of the brain. The alteration in the enzyme level, in patients with the progression of Alzheimer's disease, makes it a therapeutic target. In the present study, we developed BChE inhibitors through scaffold hopping by exploring two previously reported compounds, i.e., 1,4-bis((4-chlorophenyl) sulfonyl)-3,6-diphenylpiperazine-2,5-dione and N-(2-chlorophenyl)-4-(phenylsulfonamido)benzamide, to afford scaffold and pharmacophore fragments, respectively. The N,2-diphenyl-2-(phenylsulfonamido)acetamide derivatives, thus designed, were synthesised and screened for the inhibition of AChE and BChE enzymes. Compounds 30 and 33 were found to be most active against BChE among the derivatives, with IC50 values of 7.331 ± 0.946 and 10.964 ± 0.936 µM, respectively. The compounds displayed a non-competitive mode of inhibition along with BBB permeability and good cell viability on SH-SY5Y cell line. The molecular docking analysis of the compounds with BChE showed interactions with Trp82, Trp231, Leu286, and His438. The molecular dynamics study revealed the stability of the protein-ligand complexes.

Development of homology model, docking protocol and Machine-Learning based scoring functions for identification of Equus caballus's butyrylcholinesterase inhibitors.

Machine learning (ML), an emerging field in drug design, has the potential to predict in silico toxicity, shape-based analysis of inhibitors, scoring function (SF) etc. In the present study, a homology model, docking protocol, and a dedicated SF have been developed to identify the inhibitors of horse butyrylcholinesterase (BChE) enzyme. Horse BChE enzyme has homology with human BChE and is a substitute for the screening of in vitro inhibitors. The developed homology model was validated and the active site residues were identified from Cavityplus to generate grid box for docking. The validation of docking involved comparison of interactions of ligands co-crystallised with human BChE and the docked poses of the corresponding ligands with horse BChE. A high degree of similarity in the interaction profiles of generated poses validated the docking protocol. Scoring of ligands was further validated by docking with known BChE inhibitors. The binding energies obtained from SF was correlated with IC50 values of inhibitors through classification and regression-based methods, which indicated poor predictivity of native SF. Therefore, protein-ligand binding energy, interaction profile, and ligand descriptors were used to develop and validate the classification and regression-based models. The validated extra tree binary classifier, random forest and extra tree regression-based models were compiled as a protein-ligand SF and were made available to the users through web application and python library. ML models exhibited improved area under the curve for ROC and good correlation between the predicted and observed IC50 values, than the Autodock SF. Communicated by Ramaswamy H. Sarma.

Improved machine learning scoring functions for identification of Electrophorus electricus's acetylcholinesterase inhibitors.

Structure-based drug design (SBDD) is an important in silico technique, used for the identification of enzyme inhibitors. Acetylcholinesterase (AChE), obtained from Electrophorus electricus (ee), is widely used for the screening of AChE inhibitors. It shares structural homology with the AChE of human and other organisms. Till date, the three-dimensional crystal structure of enzyme from ee is not available that makes it challenging to use the SBDD approach for the identification of inhibitors. A homology model was developed for eeAChE in the present study, followed by its structural refinement through energy minimisation. The docking protocol was developed using a grid dimension of 84 × 66 × 72 and grid point spacing of 0.375 Å for eeAChE. The protocol was validated by redocking a set of co-crystallised inhibitors obtained from mouse AChE, and their interaction profiles were compared. The results indicated a poor performance of the Autodock scoring function. Hence, a batch of machine learning-based scoring functions were developed. The validation results displayed an accuracy of 81.68 ± 1.73% and 82.92 ± 3.05% for binary and multiclass classification scoring function, respectively. The regression-based scoring function produced [Formula: see text] and [Formula: see text] values of 0.94, 0.635 and 0.634, respectively.

Cellular and molecular influencers of neuroinflammation in Alzheimer's disease: Recent concepts & roles.

Alzheimer's disease (AD), an extremely common neurodegenerative disorder of the older generation, is one of the leading causes of death globally. Besides the conventional hallmarks i.e. Amyloid-ß (Aß) plaques and neurofibrillary tangles (NFTs), neuroinflammation also serves as a major contributing factor in the pathogenesis of AD. There are mounting evidences to support the fundamental role of cellular (microglia, astrocytes, mast cells, and T-cells) and molecular (cytokines, chemokines, caspases, and complement proteins) influencers of neuroinflammation in producing/promoting neurodegeneration and dementia in AD. Genome-wide association studies (GWAS) have revealed the involvement of various single nucleotide polymorphisms (SNPs) of genes related to neuroinflammation with the risk of developing AD. Modulating the release of the neuroinflammatory molecules and targeting their relevant mechanisms may have beneficial effects on the onset, progress and severity of the disease. Here, we review the distinct role of various mediators and modulators of neuroinflammation that impact the pathogenesis and progression of AD as well as incite further research efforts for the treatment of AD through a neuroinflammatory approach.