Abstract
Artemisinin (also known as Qinghaosu), an active component of the Qinghao extract, is widely used as antimalarial drug. Previous studies reveal that artemisinin and its derivatives also have effective anti-inflammatory and immunomodulatory properties, but the direct molecular target remains unknown. Recently, several reports mentioned that myeloid differentiation factor 2 (MD-2, also known as lymphocyte antigen 96) may be the endogenous target of artemisinin in the inhibition of lipopolysaccharide signaling. However, the exact interaction between artemisinin and MD-2 is still not fully understood. Here, experimental and computational methods were employed to elucidate the relationship between the artemisinin and its inhibition mechanism. Experimental results showed that artemether exhibit higher anti-inflammatory activity performance than artemisinin and artesunate. Molecular docking results showed that artemisinin, artesunate, and artemether had similar binding poses, and all complexes remained stable throughout the whole molecular dynamics simulations, whereas the binding of artemisinin and its derivatives to MD-2 decreased the TLR4(Toll-Like Receptor 4)/MD-2 stability. Moreover, artemether exhibited lower binding energy as compared to artemisinin and artesunate, which is in good agreement with the experimental results. Leu61, Leu78, and Ile117 are indeed key residues that contribute to the binding free energy. Binding free energy analysis further confirmed that hydrophobic interactions were critical to maintain the binding mode of artemisinin and its derivatives with MD-2.
Highlights
Toll-like receptor 4 (TLR4), as a transmembrane protein, is one of the most studied pathogen-associated molecular patterns (PAMPs) recognition receptor of the Toll-like receptor family (TLRs), and plays an important role in innate and adaptive immune responses [1,2]
Previous study showed that TLR4 can be recognized and activated by bacterial lipopolysaccharide (LPS) in association with the accessory proteins MD-2, leading to dimerization of TLR4-MD-2-LPS complex and to the release nitric oxide (NO) and proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) [10,11,12,13,14]
Atomistic molecular dynamics simulations were performed to study the dynamics and stability of these complexes obtained from the docking study
Summary
Toll-like receptor 4 (TLR4), as a transmembrane protein, is one of the most studied pathogen-associated molecular patterns (PAMPs) recognition receptor of the Toll-like receptor family (TLRs), and plays an important role in innate and adaptive immune responses [1,2]. Abnormal activation of the TLR4 signaling pathway may lead to a broad variety of diseases, including allergic diseases, autoimmune disorders, infectious diseases, cardiovascular disease, obesity-associated metabolic diseases, neuronal degeneration and inflammatory bowel diseases [3,4,5,6,7,8,9]. Previous study showed that TLR4 can be recognized and activated by bacterial lipopolysaccharide (LPS) in association with the accessory proteins MD-2, leading to dimerization of TLR4-MD-2-LPS complex and to the release nitric oxide (NO) and proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) [10,11,12,13,14]. Exploring small molecules that can competitively bind in the LPS-binding pocket of MD-2 was proposed as a way of inhibiting sustained activation and overactivation of the TLR4 signaling pathway
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