Eksplorasi inhibitor potensial diadenosin tetrafosfat hidrolase Plasmodium falciparum (PfAp4AH) dari tanaman herbal Indonesia

Abstract

Penyakit malaria memerlukan upaya pengobatan baru yang lebih efektif. Salah satunya melalui pencarian inhibitor protein yang bersifat esensial dalam siklus hidup parasit penyebab malaria, Plasmodium falciparum. Penelitian ini menargetkan diadenosin tetrafosfat hidrolase (PfAp4AH) dan ligan inhibitor dieksplorasi dari tanaman herbal Indonesia. Penentuan daerah penambatan didasarkan pada analisis druggability pocket dan tingkat konservasi pada pocket pada keberadaan residu asam amino yang tidak terkonservasi pada Ap4AH manusia (HsAp4AH) namun terdapat pada PfAp4AH (Pro133 dan Ser135). Penapisan 2099 ligan herbal secara simultan digunakan VINA pada YASARA, lalu ligan terbaik dipilih untuk divalidasi lebih lanjut menggunakan program Autodock4 melalui Google Colab. Hasil penelitian menunjukkan 14 senyawa aktif yang potensial sebagai inhibitor PfAp4AH berdasarkan analisis energi bebas ikatan (ΔG), uji bioavailabilitas serta interaksi ligan dengan Pro133 dan Ser135 pada reseptor. Senyawa cudraflavone A, 8-C-glucosyl-5-deoxykaempferol, dan calophyllic acid adalah senyawa paling potensial berdasarkan keseluruhan parameter analisis, dengan nilai ΔG berturut-turut -8.65, -8.55, dan -8.05 kkal/mol.

Malaria requires new and more effective treatment efforts. One of them is the search for protein inhibitors that are essential in the parasite's life cycle that causes malaria, Plasmodium falciparum. This study targets diadenosine tetraphosphate hydrolase (PfAp4AH) and inhibitory ligands explored from Indonesian herbal plants. The binding site determination was based on analysis of the druggability pocket and the conservation level in the pocket in the presence of amino acid residues that were not conserved in human Ap4AH (HsAp4AH) but were present in PfAp4AH (Pro133 and Ser135). VINA screened 2099 ligands simultaneously on the Yasara platform, the best ligands were selected for further validation using the Autodock4 program via Google Colab. The results showed 14 potentially active compounds as PfAp4AH inhibitors. This selection was based on the analysis of binding free energy (ΔG), bioavailability, and the interaction of the ligand with Pro133 and Ser135 at the receptor. Cudraflavone A, 8-C-glucosyl-5-deoxykaempferol, and calophyllic acid were the most potent compounds based on the overall analysis parameters, with G values of -8.65, -8.55, and -8.05 kcal/mol, respectively.