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.

Improved Pharmacokinetic and Pharmacodynamic Profile of Deuterium-Reinforced Tricyclic Antidepressants Doxepin, Dosulepin, and Clomipramine in Animal Models.

BACKGROUND AND OBJECTIVES: Doxepin, dosulepin, and clomipramine are tricyclic antidepressants (TCAs) that act as serotonin and noradrenaline reuptake inhibitors. The metabolites formed by N-dealkylation of these tricyclic antidepressants contribute to overall poor pharmacokinetics and efficacy. Deuteration of the methyl groups at metabolically active sites has been reported to be a useful strategy for developing more selective and potent antidepressants. This isotopic deuteration can lead to better bioavailability and overall effectiveness. The objective is to study the effect of site-selective deuteration of TCAs on their pharmacokinetic and pharmacodynamic profile by comparison with their nondeuterated counterparts. METHODS: In the current study, the pharmacokinetic profile and antidepressant behavior of deuterated TCAs were evaluated using the forced swim test (FST) and tail suspension test (TST), using male Wistar rats and male Swiss albino mice, respectively; additionally, a synaptosomal reuptake study was carried out. RESULTS: Compared with the nondeuterated parent drugs, deuterated forms showed improved efficacy in the behavior paradigm, indicating improved pharmacological activity. The pharmacokinetic parameters indicated increased maximum concentration in the plasma (Cmax), elimination half-life (t1/2), and area under the concentration-time curve (AUC)  in deuterated compounds. This can have a positive clinical impact on antidepressant treatment. Synaptosomal reuptake studies indicated marked inhibition of the reuptake mechanism of serotonin (5-HT) and norepinephrine. CONCLUSIONS: Deuterated TCAs can prove to be potentially better molecules in the treatment of neuropsychiatric disorders as compared with nondeuterated compounds. In addition, we have demonstrated a concept that metabolically active, site-selective deuteration can be beneficial for improving the pharmacokinetic and pharmacodynamic profiles of TCAs. A further toxicological study of these compounds is needed to validate their future clinical use.

Resveratrol attenuates early life stress induced depression in rats: Behavioural and neurochemical evidence.

PURPOSE: Maternal deprivation (MD), a severe naturalistic type of stress in the early postnatal days, is a well-established model of early life stress (ELS) that models juvenile adversity and may result in significant depressive disease in adults. In order to analyze the behavioural, brain monoamine level and HPA axis dysregulations caused by ELS and to determine whether Resveratrol (Res) could counteract these effects, Wistar rat pups were subjected to the MD paradigm, which simulated the consequences of depression. METHODS: The pups on their postnatal day 1-10 were divided in 5 groups (n = 8); nondeprived (ND), maternally deprived (DC), standard fluoxetine (FLX) (5 mg/kg i.p), Res (20, 40 mg/kg i.p). Excluding the ND group, other pups were separated from dam for 3hr/day from day 1 to 10th day. Treatment was initiated from 50th day and was given for 12 days. The behaviour parameters light/dark test, sucrose preference, and resident intruder test were employed. Serum cortisol levels, brain antioxidant activity, monoamine levels and neuronal morphology in the hippocampus were assessed. RESULTS: The MD rats showed altered behaviour, including more light-dark transitions, less desire for sucrose, and lower attack latencies. MD influenced the release of serum cortisol and interfered with monoamine, antioxidant levels as well as reduced Nissl bodies in the hippocampus. Treatment with Res led to improved behavioural functions also restored monoamine levels, reduced cortisol release, oxidative stress and prevented histopathological alterations in the rat hippocampus. CONCLUSION: Res showed neuroprotective effects by improving the brain antioxidants and monoamine levels and HPA axis dysregulation and thus improves MD induced depression like behaviour in Wistar rats.

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.