Computational insights into human UCP1 activators through molecular docking, MM-GBSA, and molecular dynamics...

Area of Science:

• Biochemistry
• Pharmacology
• Computational Chemistry

Background:

• Rising global obesity rates necessitate novel therapeutic strategies.
• Brown adipose tissue (BAT) activation of uncoupling protein 1 (UCP1) promotes thermogenesis and energy expenditure.
• Targeting UCP1 with small molecules offers a potential avenue for obesity management.

Purpose of the Study:

• To identify and evaluate potential small molecule activators of UCP1.
• To explore the binding interactions and stability of these activators with UCP1.
• To assess the pharmacological potential of identified compounds for anti-obesity applications.

Main Methods:

• Molecular docking simulations were performed to screen UCP1 activators, using 2,4-dinitrophenol (DNP) as a reference.
• Prime MM-GBSA calculations and 100-ns molecular dynamics (MD) simulations were used to assess binding affinity and complex stability.
• Physicochemical properties, including absorption, lipophilicity, and pKa, were evaluated for pharmacological relevance.

Main Results:

• Seven top-scoring compounds, including naringin and quercetin, were identified as potential UCP1 activators.
• Naringin exhibited a high binding affinity (ΔGBind of -70.48 kcal/mol) and stable complex formation with UCP1.
• Key interactions between the identified activators and UCP1 binding pocket residues were elucidated.
• Most compounds demonstrated favorable absorption and lipophilicity profiles, suggesting good pharmacological potential.

Conclusions:

• The study identified several promising small molecules that activate UCP1, offering potential for obesity treatment.
• Computational and simulation methods provided insights into UCP1-ligand interactions and compound stability.
• The findings support the development of novel UCP1-targeting therapeutics for effective obesity management.