Curcuminoid Compounds Inhibit Macrophage Migration Inhibitory Factor: In Silico Study for Their Association to Anti-diabetic Potency
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Abstract
Abstract—Diabetes mellitus is a health problem characterized by chronic inflammation causing complications in the cardiovascular, kidneys, eyes, and nervous system, with macrophage migration inhibitory factor (MIF) protein playing a crucial function in the inflammatory process chain. MIF has been known as a signaling protein involved in the development of type 1 and type 2 diabetes mellitus (DM). There are several studies indicating that the development of type 1 and type 2 DM is influenced by the accumulation of macrophages in tissues susceptible to diabetic injury or infection. Curcuminoids, the bioactive components in turmeric, are known for their ability to decrease inflammation. This in silico study is intended to analyze the potential anti-inflammatory effect of curcuminoid in DM, with a specific focus on how it may reduce proinflammatory signals through MIF. The investigation involved predicting physicochemical, pharmacokinetic and toxicity (ADMET) qualities for curcuminoids, followed by molecular docking simulations with MIF as the target protein. The ADMET results showed curcumin and bisdemethoxycurcumin had favorable properties, while dimethoxycurcumin exhibited undesirable traits like low VDss. Therefore, molecular docking simulations were performed using curcumin and bisdemethoxycurcumin as ligands. The molecular docking simulations indicated that curcumin has a negative binding affinity slightly lower than (S, R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1), a reference MIF inhibitor; and bisdemethoxycurcumin binds to MIF even stronger than ISO-1, with interacting MIF amino acids Lys 32, Ile 64 Asn 97, Pro 1, and Tyr 95. Hence, the curcumin and bisdemethoxycurcumin compounds were found as having the potential to inhibit MIF activity that is associated with the progression of DM.
Keywords: curcuminoids, diabetes melitus (dm), inflammation, mif inhibitors, molecular docking
Abstrak—Diabetes mellitus (DM) merupakan masalah kesehatan yang ditandai dengan peradangan kronis, yang dapat menyebabkan komplikasi pada sistem kardiovaskular, ginjal, mata, dan sistem saraf. Protein macrophage migration inhibitory factor (MIF) memiliki peran penting dalam proses peradangan. MIF diketahui sebagai protein pensinyalan yang terlibat dalam perkembangan DM tipe 1 dan tipe 2. Beberapa penelitian menunjukkan bahwa perkembangan DM tipe 1 dan tipe 2 dipengaruhi oleh akumulasi makrofag pada jaringan yang rentan terhadap cedera atau infeksi akibat diabetes. Kurkuminoid, komponen bioaktif dalam kunyit, dikenal memiliki kemampuan untuk meringankan peradangan. Studi in silico ini bertujuan untuk menganalisis potensi efek antiinflamasi kurkuminoid terhadap DM, dengan fokus pada kemampuannya dalam menurunkan sinyal proinflamasi melalui MIF. Studi ini mencakup prediksi sifat fisikokimia, farmakokinetik, dan toksisitas (ADMET) kurkuminoid, yang dilanjutkan dengan simulasi molecular docking menggunakan MIF sebagai protein target. Hasil analisis ADMET menunjukkan bahwa kurkumin dan bisdemetoksikurkumin memiliki sifat yang menguntungkan, sedangkan dimetoksikurkumin menunjukkan karakteristik yang kurang diinginkan, seperti volume distribusi (VDss) yang rendah. Oleh karena itu, simulasi molecular docking dilakukan dengan menggunakan kurkumin dan bisdemetoksikurkumin sebagai ligan. Hasil simulasi molecular docking menunjukkan bahwa kurkumin memiliki afinitas pengikatan yang sedikit lebih rendah dibandingkan dengan (S, R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1), senyawa referensi inhibitor MIF. Sementara itu, bisdemetoksikurkumin menunjukkan ikatan yang lebih kuat dengan MIF dibandingkan ISO-1, dengan residu asam amino MIF yang berinteraksi meliputi Lys 32, Ile 64, Asn 97, Pro 1, dan Tyr 95. Dengan demikian, senyawa kurkumin dan bisdemetoksikurkumin berpotensi menghambat aktivitas MIF yang berperan dalam perkembangan DM.
Kata kunci: kurkuminoid, diabetes melitus (dm), peradangan, inhibitor mif, molecular docking.
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