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Molecular docking analysis of marine phytochemicals with BACE-1.

ABSTRACT: Alzheimer's disease (AD), a debilitating neurodegenerative condition, is characterized by progressive cognitive decline brought about by the deposition of amyloid beta (Aβ) plaques in the brain initiates downstream neuronal dysfunction and death in AD pathogenesis. The β-secretase (BACE-1) enzyme plays a crucial role in generating Aβ from amyloid precursor protein (APP). Hence, we report the virtual screening of marine phytochemicals as BACE-1 inhibitors. 2583 compounds, retrieved from Comprehensive Marine Natural Product Database (CMNPD), were primarily screened for drug-likeliness and blood-brain barrier permeability using admetSAR 2.0 and in-house BBBper tool and resulted in a total of 635 phytochemicals, selected for further docking studies using BACE-1 as target receptor and Atabecestat as standard BACE-1 inhibitor. Seven of 635 compounds docked against BACE-1, showed better binding affinities than Atabecestat, with the red algal metabolite lactodehydrothyrsiferol showing lowest binding energy of -10.83 kcal/mol. These compounds are worth investigating further to assess their neuroprotective efficacy and pharmacokinetic properties. The study also provides a rational framework to uncover novel pharmacophores from marine sources for AD therapy acting through BACE-1 inhibition.

SUBMITTER: Sheokand D

PROVIDER: S-EPMC10941776 | biostudies-literature | 2024

REPOSITORIES: biostudies-literature

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Molecular docking analysis of marine phytochemicals with BACE-1.

Sheokand Deepak D Grewal Annu A Kumar Pawan P Chauhan Raveena R Saini Vandana V Kumar Ajit A

Bioinformation 20240229 2

Alzheimer's disease (AD), a debilitating neurodegenerative condition, is characterized by progressive cognitive decline brought about by the deposition of amyloid beta (Aβ) plaques in the brain initiates downstream neuronal dysfunction and death in AD pathogenesis. The β-secretase (BACE-1) enzyme plays a crucial role in generating Aβ from amyloid precursor protein (APP). Hence, we report the virtual screening of marine phytochemicals as BACE-1 inhibitors. 2583 compounds, retrieved from Comprehen ...[more]

PMID: 38497071

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Project description:BackgroundBeta-site amyloid precursor protein cleaving enzyme (BACE-1) is a single-membrane protein belongs to the aspartyl protease class of catabolic enzymes. This enzyme involved in the processing of the amyloid precursor protein (APP). The cleavage of APP by BACE-1 is the rate-limiting step in the amyloid cascade leading to the production of two peptide fragments Aβ40 and Aβ42. Among two peptide fragments Aβ42 is the primary species thought to be responsible for the neurotoxicity and amyloid plaque formation that lead to memory and cognitive defects in Alzheimer's disease (AD). AD is a ravaging neurodegenerative disorder for which no disease-modifying treatment is currently available. Inhibition of BACE-1 is expected to stop amyloid plaque formation and emerged as an interesting and attractive therapeutic target for AD.MethodsLigand-based computational approach was used to identify the molecular chemical features required for the inhibition of BACE-1 enzyme. A training set of 20 compounds with known experimental activity was used to generate pharmacophore hypotheses using 3D QSAR Pharmacophore Generation module available in Discovery studio. The hypothesis was validated by four different methods and the best hypothesis was utilized in database screening of four chemical databases like Maybridge, Chembridge, NCI and Asinex. The retrieved hit compounds were subjected to molecular docking study using GOLD 4.1 program.ResultsAmong ten generated pharmacophore hypotheses, Hypo 1 was chosen as best pharmacophore hypothesis. Hypo 1 consists of one hydrogen bond donor, one positive ionizable, one ring aromatic and two hydrophobic features with high correlation coefficient of 0.977, highest cost difference of 121.98 bits and lowest RMSD value of 0.804. Hypo 1 was validated using Fischer randomization method, test set with a correlation coefficient of 0.917, leave-one-out method and decoy set with a goodness of hit score of 0.76. The validated Hypo 1 was used as a 3D query in database screening and retrieved 773 compounds with the estimated activity value <100 nM. These hits were docked into the active site of BACE-1 and further refined based on molecular interactions with the essential amino acids and good GOLD fitness score.ConclusionThe best pharmacophore hypothesis, Hypo 1, with high predictive ability contains chemical features required for the effective inhibition of BACE-1. Using Hypo 1, we have identified two compounds with diverse chemical scaffolds as potential virtual leads which, as such or upon further optimization, can be used in the designing of new BACE-1 inhibitors.

Project description:IntroductionAlzheimer's disease (AD), the most predominant cause of dementia, has evolved tremendously with an escalating frequency, mainly affecting the elderly population. An effective means of delaying, preventing, or treating AD is yet to be achieved. The failure rate of dementia drug trials has been relatively higher than in other disease-related clinical trials. Hence, multi-targeted therapeutic approaches are gaining attention in pharmacological developments.AimsAs an extension of our earlier reports, we have performed docking and molecular dynamic (MD) simulation studies for the same 13 potential ligands against beta-site APP cleaving enzyme 1 (BACE-1) and γ-secretase as a therapeutic target for AD. The In-silico screening of these ligands as potential inhibitors of BACE-1 and γ-secretase was performed using AutoDock enabled PyRx v-0.8. The protein-ligand interactions were analyzed in Discovery Studio 2020 (BIOVIA). The stability of the most promising ligand against BACE-1 and γ-secretase was evaluated by MD simulation using Desmond-2018 (Schrodinger, LLC, NY, USA).ResultsThe computational screening revealed that the docking energy values for each of the ligands against both the target enzymes were in the range of -7.0 to -10.1 kcal/mol. Among the 13 ligands, 8 (55E, 6Z2, 6Z5, BRW, F1B, GVP, IQ6, and X37) showed binding energies of ≤-8 kcal/mol against BACE-1 and γ-secretase. For the selected enzyme targets, BACE-1 and γ-secretase, 6Z5 displayed the lowest binding energy of -10.1 and -9.8 kcal/mol, respectively. The MD simulation study confirmed the stability of BACE-6Z5 and γ-secretase-6Z5 complexes and highlighted the formation of a stable complex between 6Z5 and target enzymes.ConclusionThe virtual screening, molecular docking, and molecular dynamics simulation studies revealed the potential of these multi-enzyme targeted ligands. Among the studied ligands, 6Z5 seems to have the best binding potential and forms a stable complex with BACE-1 and γ-secretase. We recommend the synthesis of 6Z5 for future in-vitro and in-vivo studies.

Project description:Phytochemicals and antibacterial and antioxidant activities of Cadia purpurea roots were investigated herein for the first time. The phytochemical study led to the isolation of two compounds, di-(2-methylheptyl) phthalate (1) and 13-O-pyrrolecarboxyl lupanine (2), from methanol roots extract of C. purpurea. The antibacterial activity results revealed that the n-hexane extract presented a better inhibitory value (13.8 ± 0.0 mm) followed by chloroform (11.1 ± 0.4 mm) and chloroform : methanol (1 : 1) (10.7 ± 0.1 mm) extracts against E. coli at the maximum dose of 100 mg/mL. While, methanolic and ethanolic extracts displayed a mild activity against same bacterium at same dose. The methicillin resistant S. aureus was found with almost total resistance to all extracts up to the 100 mg/mL. The chloroform : methanol (1 : 1), chloroform, and n-hexane extracts recorded inhibition zone values (8.0 ± 0.0-10.0 ± 0.1 mm, 7.7 ± 0.0-9.8 ± 0.1 mm, and 7.3 ± 0.2-8.9 ± 0.2 mm, respectively) better than chloramphenicol (7.2 ± 0.6 mm at 30 μg dose) against P. aeruginosa. The alcoholic extracts also exhibited an activity better than chloramphenicol up to 25 mg/mL against same bacterium. Compound 2 produced a comparable inhibition value (9.6 ± 0.0 mm to 18.5 ± 0.0 mm) to that of chloramphenicol (21.5 ± 0.3 mm) against E. coli at doses up to 1.0 mg/mL; whereas, compound 1 showed a slight activity (7.1 ± 0.1 mm-10.3 ± 0.0 mm). Both compounds were found generally inactive against S. aureus, while they provided an activity better than chloramphenicol (7.2 ± 0.6 mm) against P. aeruginosa with inhibition zones ranging from 7.1 ± 0.0 mm to 9.0 ± 0.1 mm for compound 1 and 7.2 ± 0.0 mm to 10.6 ± 0.0 mm for compound 2. Ethanolic and methanolic extracts exhibited a better DPPH radical scavenging activity (IC50 values of 12.9 and 16.03 μg/mL, respectively) and strong ferric ion reducing power (with absorbance of 0.788 ± 0.000 and 0.810 ± 0.001, respectively) at a concentration of 500 μg/mL compared to the other extracts. Compound 1 also possessed a better anti-DPPH trapping activity (IC50, 7.99 μg/mL) than compound 2 (IC50, 58.34 μg/mL). The compounds, however, indicated a weak ferric ion reduction power even at higher amount. In general, the observed antibacterial and antioxidant activities of isolated compounds and extracts were found to be dose-dependent. Conducting further biochemical investigations on all parts of this plant could provide opportunities of finding extra alkaloidal compounds and other phthalate derivatives with better biological activity.

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Molecular docking analysis of marine phytochemicals with BACE-1.

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Molecular docking analysis of marine phytochemicals with BACE-1.

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