Molecular Docking and Dynamic Simulation of AZD3293 and Solanezumab Effects Against BACE1 to Treat Alzheimer's Disease

Hassan, Mubashir; Shahzadi, Saba; Seo, Sung Yum; Alashwal, Hany; Zaki, Nazar; Moustafa, Ahmed A.

doi:10.3389/fncom.2018.00034

Cited by 54 publications

(24 citation statements)

References 44 publications

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“…Amino acid residues, D106, K107 and F108 of BACE-1 active site were found to be commonly interacting with DDC2, DDC3 and AZD3293. Similarly, Hassan et al [16] observed strong hydrogen bonding of AZ3293 with K107. In another study, Rajasekhar et al [17] observed that BACE-1 inhibitors interacted with F108 amino acid of BACE-1.…”

Section: Discussionmentioning

confidence: 78%

Designing dual inhibitors for the treatment of Alzheimer’s disease as well as Type 2 diabetes mellitus via pharmacoinformatics approach: A step towards better medication for diabetes-associated neurological disorder

Hussain¹,

Rizvi²,

Subaiea³

et al. 2020

Trop. J. Pharm Res

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Purpose: To design dual inhibitors against Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM) via pharmacoinformatics approach.Methods: Dual Drug Candidates (DDC) were designed and explored for their molecular interaction with several AD and T2DM targets. Pterostilbene, a natural anti-T2DM compound was coupled with different cholinesterase inhibitors to design DDC. Orisis Datawarrior online property calculator tools, Autock 4.2 and Hex 5.1 were used to investigate the potency of all DDC relative to positive controls.Results: The study found that DDC2 (pterostilbene - methylene linker -octa hydro amino phenothiazine), DDC3 (pterostilbene - ethylene linker - N-phthalimide) and DDC5 (pterostilbene - carbonyl linker - 2-methyl-4-aminoquinoline) were the most promising out of all the DDCs. DDC2 showed strong molecular interaction with most of the AD and T2DM targets, including acetylcholinesterase, butrylcholinesterase, β-secretase, receptor for advanced glycation end products and ATP sensitive potassium channel, dipeptidyl peptidase IV and sodium glucose transport protien 2. The findings also revealed the amyloid anti-aggregation potential of DDC.Conclusion: The results show that DDC3 and DDC5 significantly interfer with the primary nucleation process of β amyloid. Thus, DDC2, DDC3 and DDC5 have strong anti-T2DM and anti-AD potential. Keywords: Type 2 Diabetes Mellitus, Alzheimer’s disease, Dual drug candidate, Amyloid-beta, Pterostilbene

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Section: Discussionmentioning

confidence: 78%

Designing dual inhibitors for the treatment of Alzheimer’s disease as well as Type 2 diabetes mellitus via pharmacoinformatics approach: A step towards better medication for diabetes-associated neurological disorder

Hussain¹,

Rizvi²,

Subaiea³

et al. 2020

Trop. J. Pharm Res

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“…Molecular docking experiment is best approach to study the binding conformation of ligands within the active region of target proteins . To predict the best‐fitted conformational position, the synthesized compounds, 8a–k , were docked against alkaline phosphatase.…”

Section: Resultsmentioning

confidence: 99%

Bi‐heterocyclic benzamides as alkaline phosphatase inhibitors: Mechanistic comprehensions through kinetics and computational approaches

Abbasi

Nazir

Ur-Rehman

et al. 2019

Archiv der Pharmazie

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Novel bi‐heterocyclic benzamides were synthesized by sequentially converting 4‐(1H‐indol‐3‐yl)butanoic acid (1) into ethyl 4‐(1H‐indol‐3‐yl)butanoate (2), 4‐(1H‐indol‐3‐yl)butanohydrazide (3), and a nucleophilic 5‐[3‐(1H‐indol‐3‐yl)propyl]‐1,3,4‐oxadiazole‐2‐thiol (4). In a parallel series of reactions, various electrophiles were synthesized by reacting substituted anilines (5a–k) with 4‐(chloromethyl)benzoylchloride (6) to afford 4‐(chloromethyl)‐N‐(substituted‐phenyl)benzamides (7a–k). Finally, the nucleophilic substitution reaction of 4 was carried out with newly synthesized electrophiles, 7a–k, to acquire the targeted bi‐heterocyclic benzamides, 8a–k. The structural confirmation of all the synthesized compounds was done by IR, 1H NMR, 13C NMR, EI‐MS, and CHN analysis data. The inhibitory effects of these bi‐heterocyclic benzamides (8a–k) were evaluated against alkaline phosphatase, and all these molecules were identified as potent inhibitors relative to the standard used. The kinetics mechanism was ascribed by evaluating the Lineweaver–Burk plots, which revealed that compound 8b inhibited alkaline phosphatase non‐competitively to form an enzyme–inhibitor complex. The inhibition constant Ki calculated from Dixon plots for this compound was 1.15 μM. The computational study was in full agreement with the experimental records and these ligands exhibited good binding energy values. These molecules also exhibited mild cytotoxicity toward red blood cell membranes when analyzed through hemolysis. So, these molecules might be deliberated as nontoxic medicinal scaffolds to render normal calcification of bones and teeth.

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“…A molecular docking experiment is the best approach to study the binding conformation of ligands against target protein [53][54][55] . The binding pocket analysis showed that deltamethrin and permethrin were confined in the active region of a-glucosidase.…”

Section: Binding Pocket and Deltamethrin And Permethrin Binding Conformationsmentioning

confidence: 99%

Diaryl azo derivatives as anti-diabetic and antimicrobial agents: synthesis, in vitro, kinetic and docking studies

Tahir

Shahzad

Tabassum

et al. 2021

Journal of Enzyme Inhibition and Medicinal Chemistry

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In the present study, a series of azo derivatives (TR-1 to TR-9) have been synthesised via the diazo-coupling approach between substituted aromatic amines with phenol or naphthol derivatives. The compounds were evaluated for their therapeutic applications against alpha-glucosidase (anti-diabetic) and pathogenic bacterial strains E. coli (gram-negative), S. aureus (gram-positive), S. aureus (gram-positive) drug-resistant strain, P. aeruginosa (gram-negative), P. aeruginosa (gram-negative) drug-resistant strain and P. vulgaris (gram-negative). The IC 50 (mg/mL) of TR-1 was found to be most effective (15.70 ± 1.3 mg/mL) compared to the reference drug acarbose (21.59 ± 1.5 mg/mL), hence, it was further selected for the kinetic studies in order to illustrate the mechanism of inhibition. The enzyme inhibitory kinetics and mode of binding for the most active inhibitor (TR-1) was performed which showed that the compound is a noncompetitive inhibitor and effectively inhibits the target enzyme by binding to its binuclear active site reversibly.

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Molecular Docking and Dynamic Simulation of AZD3293 and Solanezumab Effects Against BACE1 to Treat Alzheimer's Disease

Cited by 54 publications

References 44 publications

Designing dual inhibitors for the treatment of Alzheimer’s disease as well as Type 2 diabetes mellitus via pharmacoinformatics approach: A step towards better medication for diabetes-associated neurological disorder

Designing dual inhibitors for the treatment of Alzheimer’s disease as well as Type 2 diabetes mellitus via pharmacoinformatics approach: A step towards better medication for diabetes-associated neurological disorder

Bi‐heterocyclic benzamides as alkaline phosphatase inhibitors: Mechanistic comprehensions through kinetics and computational approaches

Diaryl azo derivatives as anti-diabetic and antimicrobial agents: synthesis, in vitro, kinetic and docking studies

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