TARGETS FOR MOLECULAR MODELING & THEIR WORKING MECHANISMS

 TARGETS FOR MOLECULAR MODELING & THEIR WORKING MECHANISMS

Our group has chosen Flavanones, the subclass of Flavonoids for the study of anti-diabetic properties. Flavanones are highly concentrated in citrus fruits. Flavanones will be discussed extensively later in this thesis. 3 targets were selected for the molecular modeling. This portion will highlight their structure, property, binding site, and responses after activation.

3 Targets are as follows:-

❖ AMPK (Adenosine monophosphate-activated protein kinase) ❖ Human Salivary alpha-amylase (SAA) ❖ Human Pancreatic alpha-amylase

AMPK (Adenosine monophosphate-activated protein kinase)

AMP-activated protein kinase (AMPK) serves as a vital cellular energy sensor and regulator in both the central nervous system and peripheral organs. In conditions of energy depletion. When energy levels are low, such as during exercise or starvation, this heterotrimeric protein becomes activated. It then sends signals to promote ATP-generating processes while inhibiting ATP-consuming processes. AMPK activation plays a crucial role in restoring energy balance. Within the hypothalamus, AMPK contributes to energy homeostasis by promoting feeding behavior to increase energy intake, enhancing glucose production, and reducing thermogenesis to decrease energy output. Hormones also interact with AMPK to modulate their central effects on appetite regulation and thermogenic influences. Understanding the factors influencing hypothalamic AMPK activity and the underlying mechanisms is essential to comprehend the role of central AMPK in energy balance maintenance. This knowledge helps shed light on the physiological effects of hypothalamic AMPK in restoring energy balance.

The structure of AMP-activated protein kinase (AMPK):- It is composed of three subunits: α, β, and γ. Each subunit plays a specific role in the structure, function, and regulation of AMPK. Here's a detailed explanation of the structure of AMPK12: α-Subunit: The α-subunit is the largest subunit of AMPK and contains the catalytic domain responsible for the kinase activity of the enzyme. It consists of two distinct kinase domains, known as the α-kinase domains, connected by a flexible linker region. These domains are involved in phosphorylating downstream targets. The α-subunit also contains an auto inhibitory domain, which helps regulate the activity of the catalytic domains. When AMPK is inactive, this domain interacts with the catalytic domains, restricting their kinase activity. The binding of AMP or ADP to the γ-subunit relieves this auto inhibition, allowing for activation of the kinase activity. β-Subunit: The β-subunit acts as a scaffold within the AMPK complex. It provides structural support and helps stabilize the trimetric structure. The β-subunit has a glycogen-binding domain, which allows AMPK to interact with glycogen particles. This interaction is important for regulating glycogen metabolism and storage. The β-subunit also participates in the binding of various regulatory proteins, contributing to the proper localization and function of AMPK.

γ-Subunit:

The γ-subunit is responsible for sensing changes in cellular energy status. It

contains four cystathionine β-synthase (CBS) domains, which form a tandem

repeat structure involved in nucleotide binding. The γ-subunit has multiple

nucleotide-binding sites, including sites for AMP, ADP, and ATP. The binding

of AMP or ADP to the γ-subunit promotes the activation of AMPK by

inducing conformational changes in the complex. These changes relieve the

auto inhibition of the α-subunit and enhance the kinase activity. Conversely,

the binding of ATP to the γ-subunit inhibits AMPK activity.

The γ-subunit also contains two regulatory phosphorylation sites: Ser108 and

Ser182. Phosphorylation of these sites by upstream kinases, such as LKB1 and

CaMKKβ, further enhances the activation of AMPK