Su Hui Seong1, Manh Tuan Ha2, Byung Sun Min2, Hyun Ah Jung3, Jae Sue Choi4. 1. Department of Food and Life Science, Pukyong National University, Busan 48513, Republic of Korea. 2. College of Pharmacy, Drug Research and Development Center, Daegu Catholic University, Gyeongbuk 38430, Republic of Korea. 3. Department of Food Science and Human Nutrition, Chonbuk National University, Jeonju 54896, Republic of Korea. Electronic address: jungha@jbnu.ac.kr. 4. Department of Food and Life Science, Pukyong National University, Busan 48513, Republic of Korea. Electronic address: choijs@pknu.ac.kr.
Abstract
AIMS: Morus, a member of the family Moraceae and commonly known as the mulberry, comprises a pharmaceutically important plant group whose major constituents are the moracins. Moracin derivatives have received great attention because they exhibit a diverse range of biological functionalities. However, no studies have considered the anti-Alzheimer's disease (AD) and anti-glycation potential of moracin derivatives. MAIN METHODS: We designed the current study to explore the anti-AD activity of moracin derivatives via in vitro inhibition of BACE1 and cholinesterase, their antioxidant activity via scavenging ONOO- and ABTS+ radicals, and their anti-diabetic activity through inhibition of advanced glycation end-products (AGEs) formation. Moreover, to define the mechanism of action of moracin derivatives in depth, we performed in silico molecular modeling using a computer-assisted drug design and modeling program. KEY FINDINGS: Among the four Morus-derived moracins tested, moracin S, which has a prenyl moiety in the 2-aryl benzofuran scaffold, possessed the highest BACE1 inhibitory activity. It also, in a dose-dependent fashion, decreased ONOO--mediated bovine serum albumin (BSA) nitration and formation of AGEs and amyloid cross-β structures in the glycated BSA system, and it showed notable radical scavenging activity. In addition, enzyme kinetic and molecular docking studies demonstrated that moracin S is a potent, competitive BACE1 inhibitor that could interact with key catalytic aspartyl residues. SIGNIFICANCE: The prenyl moiety in the 2-aryl benzofuran structure plays a crucial role in inhibition of BACE1. These in vitro and in silico results provide valuable information for the design of anti-AD drugs.
AIMS: Morus, a member of the family Moraceae and commonly known as the mulberry, comprises a pharmaceutically important plant group whose major constituents are the moracins. Moracin derivatives have received great attention because they exhibit a diverse range of biological functionalities. However, no studies have considered the anti-Alzheimer's disease (AD) and anti-glycation potential of moracin derivatives. MAIN METHODS: We designed the current study to explore the anti-AD activity of moracin derivatives via in vitro inhibition of BACE1 and cholinesterase, their antioxidant activity via scavenging ONOO- and ABTS+ radicals, and their anti-diabetic activity through inhibition of advanced glycation end-products (AGEs) formation. Moreover, to define the mechanism of action of moracin derivatives in depth, we performed in silico molecular modeling using a computer-assisted drug design and modeling program. KEY FINDINGS: Among the four Morus-derived moracins tested, moracin S, which has a prenyl moiety in the 2-aryl benzofuran scaffold, possessed the highest BACE1 inhibitory activity. It also, in a dose-dependent fashion, decreased ONOO--mediated bovineserum albumin (BSA) nitration and formation of AGEs and amyloid cross-β structures in the glycated BSA system, and it showed notable radical scavenging activity. In addition, enzyme kinetic and molecular docking studies demonstrated that moracin S is a potent, competitive BACE1 inhibitor that could interact with key catalytic aspartyl residues. SIGNIFICANCE: The prenyl moiety in the 2-aryl benzofuran structure plays a crucial role in inhibition of BACE1. These in vitro and in silico results provide valuable information for the design of anti-AD drugs.
Authors: Srijan Shrestha; Su Hui Seong; Seul Gi Park; Byung Sun Min; Hyun Ah Jung; Jae Sue Choi Journal: Molecules Date: 2019-08-09 Impact factor: 4.411