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Molecular Docking of Pepstatin (A) and Compounds with Structural Similarity to the Molecular Model of Human BACE-1 Enzyme

Article

Last updated: 23 Dec 2024

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Tags

Section B: Pharmaceutical Analytical & Organic Chemistry, Medicinal & Biochemistry

Abstract

Background and Objectives: Almost all known aspartic proteases are inhibited by pepstatin (A). One of the aspartic proteases enzymes, β-secretase, is a well-known enzyme in the process of Alzheimer's disease, and it plays a role in the progression of Alzheimer's disease by cleaving the amyloid precursor protein and forming the amyloid-β (Aβ) peptide. In the present study, we attempt to use pepstatin (A) and compounds with a similar structure as inhibitory ligand for β-secretase enzyme model [PDB ID: 6EQM]. Materials and Methods: We prepared the molecular model of pepstatin (A) and compounds with a similar structure, then calculated their physicochemical and pharmacological properties, and then performed molecular docking between the molecular model of human BACE-1 enzyme [PDB ID: 6EQM] with pepstatin (A) inhibitor and compounds with a similar structure. We perform molecular dynamics analysis to evaluate the deformation and fluctuation of the enzyme model with or without ligands during molecular dynamic simulation. Results: In this study, cyclic peptides and pseudo-peptides often have higher binding affinity for the active site of the enzyme in the molecular model of beta-secretase [PDB ID: 6EQM], but they have higher molecular weight than the rest of the compounds (400-700 Daltons), which consist of compounds with CID numbers: 10532731, 16084771, 122177562, 155209842, 155228360, 155228472, 155228476, 162667790, 163186155, and 164960792. Other compounds weighing between 300 and 400 Da with lower affinity were also investigated in this study, including the pseudo-peptide Ac-Ser-Sta (3R, 4R)-Val-OH with the CID numbers: 101039397 with a molecular weight of 402.4 and a docking score of -143.6, and compound 58057434 with a molecular weight of 386.4 and a docking score of -141.1, which had the highest affinity for the active site of the molecular model of human BACE-1 enzyme [PDB ID: 6EQM] in rang of 300-400 Da. Conclusion: The present study demonstrated that by using the molecular docking method and with a more comprehensive view, more effective compounds can be proposed to inhibit beta-secretase enzyme. As in our study based on molecular docking results, compounds such as pepstatin and compounds with structural similarity to it often have high affinity for the active site of beta-secretase enzyme.

DOI

10.21608/aprh.2023.219909.1223

Keywords

Molecular docking, pepstatin (A), human BACE-1

Authors

First Name

Roohallah

Last Name

Yousefi

MiddleName

-

Affiliation

Department of Biochemistry, Faculty of Biology of Tarbit Modares University, Tehran, Iran.

Email

r.yosefi@modares.ac.ir

City

Behbahan

Orcid

0000-0002-1547-6752

First Name

Roohallah

Last Name

Mokarmian

MiddleName

-

Affiliation

Behbahan Faculty of Medical Sciences, Behbahan, Iran.

Email

shahla.mokarmian@gmail.com

City

Behbahan

Orcid

0000-0001-9902-2127

First Name

Ali

Last Name

Jamshidi

MiddleName

-

Affiliation

Department of Biochemistry, Faculty of Biology of Tarbit Modares University, Tehran, Iran.

Email

ajamshidi@behums.ac.ir

City

Behbahan

Orcid

0000-0002-8615-0004

Volume

7

Article Issue

4

Related Issue

44185

Issue Date

2023-10-01

Receive Date

2023-06-25

Publish Date

2023-10-01

Page Start

181

Page End

198

Print ISSN

2357-0547

Online ISSN

2357-0539

Link

https://aprh.journals.ekb.eg/article_323438.html

Detail API

https://aprh.journals.ekb.eg/service?article_code=323438

Order

1

Type

Research Article

Type Code

318

Publication Type

Journal

Publication Title

Journal of Advanced Pharmacy Research

Publication Link

https://aprh.journals.ekb.eg/

MainTitle

Molecular Docking of Pepstatin (A) and Compounds with Structural Similarity to the Molecular Model of Human BACE-1 Enzyme

Details

Type

Article

Created At

23 Dec 2024