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Computational Studies to Understand the Neuroprotective Mechanism of Action Basil Compounds.

ABSTRACT: Neurodegenerative diseases, such as Alzheimer's and Parkinson's, pose a significant global health challenge, emphasizing the need for novel neuroprotective agents. Basil (Ocimum spp.) has been recognized for its therapeutic potential, and numerous studies have reported neuroprotective effects. In this manuscript, we present a computational protocol to extricate the underlying mechanism of action of basil compounds in neuroprotective effects. Molecular docking-based investigation of the chemical interactions between selected bioactive compounds from basil and key neuroprotective targets, including AChE, GSK3β, γ-secretase, and sirtuin2. Our results demonstrate that basil compound myricerone caffeoyl ester possesses a high affinity of -10.01 and -8.85 kcal/mol against GSK3β and γ-secretase, respectively, indicating their potential in modulating various neurobiological processes. Additionally, molecular dynamics simulations were performed to explore the protein-ligand complexes' stability and to analyze the bound basil compounds' dynamic behavior. This comprehensive computational investigation enlightens the putative mechanistic basis for the neuroprotective effects of basil compounds, providing a rationale for their therapeutic use in neurodegenerative disorders after further experimental validation.

SUBMITTER: Singh V

PROVIDER: S-EPMC10609097 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Computational Studies to Understand the Neuroprotective Mechanism of Action Basil Compounds.

Singh Varinder V Mujwar Somdutt S Singh Manjinder M Singh Tanveer T Ahmad Sheikh F SF

Molecules (Basel, Switzerland) 20231010 20

Neurodegenerative diseases, such as Alzheimer's and Parkinson's, pose a significant global health challenge, emphasizing the need for novel neuroprotective agents. Basil (<i>Ocimum</i> spp.) has been recognized for its therapeutic potential, and numerous studies have reported neuroprotective effects. In this manuscript, we present a computational protocol to extricate the underlying mechanism of action of basil compounds in neuroprotective effects. Molecular docking-based investigation of the ch ...[more]

PMID: 37894484

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Project description:Coordinating with others is part of our everyday experience. Previous studies using sensorimotor coordination games suggest that human dyads develop coordination strategies that can be interpreted as Nash equilibria. However, if the players are uncertain about what their partner is doing, they develop coordination strategies which are robust to the actual partner's actions. This has suggested that humans select their actions based on an explicit prediction of what the partner will be doing-a partner model-which is probabilistic by nature. However, the mechanisms underlying the development of a joint coordination over repeated trials remain unknown. Very much like sensorimotor adaptation of individuals to external perturbations (eg force fields or visual rotations), dynamical models may help to understand how joint coordination develops over repeated trials. Here we present a general computational model-based on game theory and Bayesian estimation-designed to understand the mechanisms underlying the development of a joint coordination over repeated trials. Joint tasks are modeled as quadratic games, where each participant's task is expressed as a quadratic cost function. Each participant predicts their partner's next move (partner model) by optimally combining predictions and sensory observations, and selects their actions through a stochastic optimization of its expected cost, given the partner model. The model parameters include perceptual uncertainty (sensory noise), partner representation (retention rate and internale noise), uncertainty in action selection and its rate of decay (which can be interpreted as the action's learning rate). The model can be used in two ways: (i) to simulate interactive behaviors, thus helping to make specific predictions in the context of a given joint action scenario; and (ii) to analyze the action time series in actual experiments, thus providing quantitative metrics that describe individual behaviors during an actual joint action. We demonstrate the model in a variety of joint action scenarios. In a sensorimotor version of the Stag Hunt game, the model predicts that different representations of the partner lead to different Nash equilibria. In a joint two via-point (2-VP) reaching task, in which the actions consist of complex trajectories, the model captures well the observed temporal evolution of performance. For this task we also estimated the model parameters from experimental observations, which provided a comprehensive characterization of individual dyad participants. Computational models of joint action may help identifying the factors preventing or facilitating the development of coordination. They can be used in clinical settings, to interpret the observed behaviors in individuals with impaired interaction capabilities. They may also provide a theoretical basis to devise artificial agents that establish forms of coordination that facilitate neuromotor recovery.

Project description:Leishmaniasis is a disease impacting public health worldwide due to its high incidence, morbidity and mortality. Available treatments are costly, lengthy and toxic, not to mention the problem of parasite resistance. The development of alternative treatments is warranted and natural products demonstrate promising activity. This study investigated the activity of Connarus suberosus extracts and compounds against Leishmania species. Several C. suberosus extracts were tested against L. amazonensis promastigotes. Active and inactive extracts were analyzed by UHPLC-MS and data evaluated using a metabolomics platform, revealing an unknown neoflavonoid (connarin, 3), isolated together with the pterocarpans: hemileiocarpin (1) and leiocarpin (2). The aforementioned compounds (1-3), together with the benzoquinones: rapanone (4), embelin (5) and suberonone (6) previously isolated by our group from the same species, were tested against: (i) L. amazonensis and L. infantum promastigotes, and (ii) L. amazonensis intracellular amastigotes, with the most active compound (3) also tested against L. infantum amastigotes. Cytotoxicity against murine peritoneal macrophages was also investigated. Compounds 2 and 3 presented an IC50 33.8 μM and 11.4 μM for L. amazonensis promastigotes; and 44.3 μM and 13.3 μM for L. infantum promastigotes, respectively. For L. amazonensis amastigotes, the IC50 of 2 was 20.4 μM with a selectivity index (SI) of 5.7, while the IC50 of 3 was 2.9 μM with an SI of 6.3. For L. infantum amastigotes, the IC50 of 3 was 7.7 μM. Compounds 2 and 3 presented activity comparable with the miltefosine positive control, with compound 3 found to be 2-4 times more active than the positive control, depending on the Leishmania species and form. The extracts and isolated compounds showed moderate toxicity against macrophages. Compounds 2 and 3 altered the mitochondrial membrane potential (ΔΨm) and neutral lipid body accumulation, while 2 also impacted plasma membrane permeabilization, culminating in cellular disorder and parasite death. Transmission electron microscopy of L. amazonensis promastigotes treated with compound 3 confirmed the presence of lipid bodies. Leiocarpin (2) and connarin (3) demonstrated antileishmanial activity. This study provides knowledge of natural products with antileishmanial activity, paving the way for prototype development to fight this neglected tropical disease.

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Computational Studies to Understand the Neuroprotective Mechanism of Action Basil Compounds.

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Computational Studies to Understand the Neuroprotective Mechanism of Action Basil Compounds.

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