Abstract
Adipocyte fatty-acid binding protein (A-FABP) is an important target of drug designs treating some diseases related to lipid-mediated biology. Molecular dynamics (MD) simulations coupled with solvated interaction energy method (SIE) were carried out to study the binding modes of three inhibitors 8CA, F8A and I4A to A-FABP. The rank of our predicted binding affinities is in accordance with experimental data. The results show that the substitution in the position 5 of N-benzyl and the seven-membered ring of N-benzyl-indole carboxylic acids strengthen the I4A binding, while the substitution in the position 2 of N-benzyl weakens the F8A binding. Computational alanine scanning and dynamics analyses were performed and the results suggest that the polar interactions of the positively charged residue R126 with the three inhibitors provide a significant contribution to inhibitor bindings. This polar interaction induces the disappearance of the correlated motion of the C terminus of A-FABP relative to the N terminus and favors the stability of the binding complex. This study is helpful for the rational design of potent inhibitors within the fields of metabolic disease, inflammation and atherosclerosis.
Highlights
Fatty acid binding proteins are small cytoplasmic proteins that are expressed in a tissue-specific manner [1]
The previous published works show that Adipocyte fatty-acid binding protein (A-FABP) can perform an important function in certain specific aspects of the metabolic syndrome and cardiovascular disease [6,7,8]
Some studies on AFABP function of mouse model suggested that functional disruption and deletion of A-FABP reduce risk of atherosclerosis in apolipoprotein E-deficient mice [1,6,9], and inhibit development of diet-induced insuline resistence [3,6,10]
Summary
Fatty acid binding proteins are small cytoplasmic proteins that are expressed in a tissue-specific manner [1]. FABPs involve lipid-mediated biology such as signaling pathways trafficking and membrane synthesis [3,4]. Adipocyte FABP is one of the nine known FABP isoforms, and highly expressed in adipose tissue and macrophages [5]. The previous published works show that A-FABP can perform an important function in certain specific aspects of the metabolic syndrome and cardiovascular disease [6,7,8]. Reductions of A-FABP in adipose issue of human induced a lower risk of hypertriglyceridemia, type 2 diabetes and coronary heart disease [11,12,13]. A-FABP was considered as an important target of drug designs treating some diseases related to lipid-mediated biology
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