KAJIAN DOCKING DAN PREDIKSI BEBERAPA ASPEK FARMAKOKINETIKA DESAIN MOLEKUL TURUNAN KUININ SEBAGAI UPAYA MENEMUKAN KANDIDAT SENYAWA ANTIMALARIA YANG BARU
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ABSTRAK
Kuinin merupakan obat antimalaria dengan t½ eliminasi yang panjang, mencapai 11-18 jam, serta memiliki berbagai efek samping yang cukup berat. Dikaitkan dengan struktur dan sifat fisikokimianya, hal tersebut dapat disebabkan tingginya lipofilisitas kuinin dan metabolitnya serta kemungkinan afinitas senyawa tersebut terhadap reseptor tertentu, di luar target kerja pada plasmodium. Penelitian ini bertujuan untuk memperoleh desain turunan kuinin yang memiliki aktivitas antimalaria setara atau lebih baik dari kuinin dengan efek samping yang lebih ringan menggunakan metode molecular modeling, terkhususnya kajian docking antara ligan dengan target. Desain turunan kuinin dilakukan melalui substitusi atom hidrogen pada cincin kuinolin dengan gugus fungsi polar, mencakup gugus -OH, -COOH, dan -SO3H. Ferriprotoporfirin IX digunakan sebagai target kerja antimalaria dan reseptor muskarinik M2 sebagai target kerja lain yang diperkirakan menyebabkan efek samping. Beberapa aspek farmakokinetika desain turunan kuinin yang diperoleh diprediksi secara kualitatif menggunakan aturan Lipinski, dan secara kuantitatif menggunakan program PreADMET, terdiri dari parameter absorpsi, distribusi serta reabsorpsi di ginjal. Telah diperoleh 4 desain senyawa turunan kuinin yang potensial yaitu kuinin tersubstitusi -OH pada atom C7’, kuinin tersubtitusi -COOH pada atom C5’ dan -OH pada atom C6’, kuinin tersubtitusi –SO3H pada atom C8’ serta kuinin tersubtitusi -SO3H pada atom C8’ dan -OH pada atom C6’.
Kata kunci : antimalaria, docking, ferriprotoporfirin IX, kuinin.
ABSTRACT
Quinine is an antimalarial drug with a long elimination half-life (t ½), about 11-18 hours and variuos severe side effects. Considering the structure and physico-chemical properties of quinine, those side effects and toxicities might be related with high lipophilicity of quinine and its metabolites and their probable affinities on certain receptor in addition to work target in plasmodium. This study aims to obtain designs of quinine derivatives having equivalent or better antimalarial activities with lesser side effects applying molecular modeling method, especially docking study between ligand and target. Quinine derivatives were designed by substitution of hydrogen atoms of different positions in the quinoline ring with three different polar functional groups, including –OH, -COOH, and -SO3H. Ferriprotoporphyrin IX was chosen as work target in plasmodium, while M2 muscarinic receptor was used as additional work target predicted to be responsible for side effects. Pharmacokinetic aspects of quinine derivatives designs were qualitatively predicted by Lipinski’s rules of five and quantitatively by online PreADMET program, including absorption, distribution, and reabsorption in kidney. 4 compound designs were obtained and predicted to be potential candidates, including quinine substituted with -OH at C7' atom, quinine substituted with –COOH at C5’ and –OH at C6’ atoms, quinine substituted with –SO3H at C8’ and quinine substituted with -SO3H at C8’ and –OH at C6’ atoms.
Key words : antimalarial drug, docking, ferriprotoporphyrin IX, lipophilicity
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