Scaffold Morphing and In Silico Design of Potential BACE-1 (β-Secretase) Inhibitors: A Hope for a Newer Dawn in Anti-Alzheimer Therapeutics
Alzheimer’s disease (AD) is the prime cause of 65–80% of dementia cases and is caused by plaque and tangle deposition in the brain neurons leading to brain cell degeneration. β-secretase (BACE-1) is a key enzyme responsible for depositing extracellular plaques made of β-amyloid protein. Therefore, e...
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MDPI AG
2023-08-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/28/16/6032 |
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| author | Shiveena Bhatia Manjinder Singh Pratibha Sharma Somdutt Mujwar Varinder Singh Krishna Kumar Mishra Thakur Gurjeet Singh Tanveer Singh Sheikh Fayaz Ahmad |
| author_facet | Shiveena Bhatia Manjinder Singh Pratibha Sharma Somdutt Mujwar Varinder Singh Krishna Kumar Mishra Thakur Gurjeet Singh Tanveer Singh Sheikh Fayaz Ahmad |
| author_sort | Shiveena Bhatia |
| collection | DOAJ |
| description | Alzheimer’s disease (AD) is the prime cause of 65–80% of dementia cases and is caused by plaque and tangle deposition in the brain neurons leading to brain cell degeneration. β-secretase (BACE-1) is a key enzyme responsible for depositing extracellular plaques made of β-amyloid protein. Therefore, efforts are being applied to develop novel BACE-1 enzyme inhibitors to halt plaque build-up. In our study, we analyzed some Elenbecestat analogues (a BACE-1 inhibitor currently in clinical trials) using a structure-based drug design and scaffold morphing approach to achieve a superior therapeutic profile, followed by in silico studies, including molecular docking and pharmacokinetics methodologies. Among all the designed compounds, SB306 and SB12 showed good interactions with the catalytic dyad motifs (Asp228 and Asp32) of the BACE-1 enzyme with drug-likeliness properties and a high degree of thermodynamic stability confirmed by the molecular dynamic and stability of the simulated system indicating the inhibitory nature of the SB306 and SB12 on BACE 1. |
| first_indexed | 2024-03-10T23:41:11Z |
| format | Article |
| id | doaj.art-1613ec21831244c8976cc2c2eb27f701 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T23:41:11Z |
| publishDate | 2023-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-1613ec21831244c8976cc2c2eb27f7012023-11-19T02:23:42ZengMDPI AGMolecules1420-30492023-08-012816603210.3390/molecules28166032Scaffold Morphing and In Silico Design of Potential BACE-1 (β-Secretase) Inhibitors: A Hope for a Newer Dawn in Anti-Alzheimer TherapeuticsShiveena Bhatia0Manjinder Singh1Pratibha Sharma2Somdutt Mujwar3Varinder Singh4Krishna Kumar Mishra5Thakur Gurjeet Singh6Tanveer Singh7Sheikh Fayaz Ahmad8Chitkara College of Pharmacy, Chitkara University, Rajpura 140401, Punjab, IndiaChitkara College of Pharmacy, Chitkara University, Rajpura 140401, Punjab, IndiaChitkara College of Pharmacy, Chitkara University, Rajpura 140401, Punjab, IndiaChitkara College of Pharmacy, Chitkara University, Rajpura 140401, Punjab, IndiaDepartment of Pharmaceutical Sciences and Technology, Maharaja Ranjit Singh Punjab Technical University, Bathinda 151001, Punjab, IndiaChitkara University Institute of Engineering and Technology, Chitkara University, Rajpura 140401, Punjab, IndiaChitkara College of Pharmacy, Chitkara University, Rajpura 140401, Punjab, IndiaDepartment of Neuroscience and Experimental Therapeutics, College of Medicine, Texas A&M Health Science Center, College Station, TX 77807, USADepartment of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi ArabiaAlzheimer’s disease (AD) is the prime cause of 65–80% of dementia cases and is caused by plaque and tangle deposition in the brain neurons leading to brain cell degeneration. β-secretase (BACE-1) is a key enzyme responsible for depositing extracellular plaques made of β-amyloid protein. Therefore, efforts are being applied to develop novel BACE-1 enzyme inhibitors to halt plaque build-up. In our study, we analyzed some Elenbecestat analogues (a BACE-1 inhibitor currently in clinical trials) using a structure-based drug design and scaffold morphing approach to achieve a superior therapeutic profile, followed by in silico studies, including molecular docking and pharmacokinetics methodologies. Among all the designed compounds, SB306 and SB12 showed good interactions with the catalytic dyad motifs (Asp228 and Asp32) of the BACE-1 enzyme with drug-likeliness properties and a high degree of thermodynamic stability confirmed by the molecular dynamic and stability of the simulated system indicating the inhibitory nature of the SB306 and SB12 on BACE 1.https://www.mdpi.com/1420-3049/28/16/6032Alzheimer’s diseaseβ-secretaseβ-amyloidBACE-1dementiaelenbecestat |
| spellingShingle | Shiveena Bhatia Manjinder Singh Pratibha Sharma Somdutt Mujwar Varinder Singh Krishna Kumar Mishra Thakur Gurjeet Singh Tanveer Singh Sheikh Fayaz Ahmad Scaffold Morphing and In Silico Design of Potential BACE-1 (β-Secretase) Inhibitors: A Hope for a Newer Dawn in Anti-Alzheimer Therapeutics Molecules Alzheimer’s disease β-secretase β-amyloid BACE-1 dementia elenbecestat |
| title | Scaffold Morphing and In Silico Design of Potential BACE-1 (β-Secretase) Inhibitors: A Hope for a Newer Dawn in Anti-Alzheimer Therapeutics |
| title_full | Scaffold Morphing and In Silico Design of Potential BACE-1 (β-Secretase) Inhibitors: A Hope for a Newer Dawn in Anti-Alzheimer Therapeutics |
| title_fullStr | Scaffold Morphing and In Silico Design of Potential BACE-1 (β-Secretase) Inhibitors: A Hope for a Newer Dawn in Anti-Alzheimer Therapeutics |
| title_full_unstemmed | Scaffold Morphing and In Silico Design of Potential BACE-1 (β-Secretase) Inhibitors: A Hope for a Newer Dawn in Anti-Alzheimer Therapeutics |
| title_short | Scaffold Morphing and In Silico Design of Potential BACE-1 (β-Secretase) Inhibitors: A Hope for a Newer Dawn in Anti-Alzheimer Therapeutics |
| title_sort | scaffold morphing and in silico design of potential bace 1 β secretase inhibitors a hope for a newer dawn in anti alzheimer therapeutics |
| topic | Alzheimer’s disease β-secretase β-amyloid BACE-1 dementia elenbecestat |
| url | https://www.mdpi.com/1420-3049/28/16/6032 |
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