Computational Study of Triterpenoids of Ganoderma lucidum with Aspartic Protease Enzymes for Discovering HIV-1 and Plasmepsin Inhibitors

Abstract

Rapid resistance development of HIV-1 and Plasmodium falciparum parasite requires discovery of more potent new drugs. Aspartic protease enzymes expressed by HIV-1 and P. falciparum could be used as important drug targets. The catalytic site is located at the bottom of a cleft in the enzyme surface and consists of triad Asp25, Thr26, Gly27. Important aspartic acids are Asp32 and Asp215. Aspartic proteases are inhibited by pepstatin-A, a naturally occurring peptide containing two statins, which replace the amino acids. The hydroxyl group of the statin binds tightly to the catalytically-active aspartic acid residues in the active site of protease, thereby mimicking the transition state of the peptide cleavage. Previous study proved that ganoderiol-F, a triterpenoid isolated from the stem of Ganoderma sinense showed higher affinity towards HIV-1 protease (binding energy= -11.40 kcal/mol and K i = 4.68 nM) than to plasmepsin I (binding energy= -9.96 kcal/mol and K i = 50.94 nM). In this paper, computational studies of G. lucidum triterpenoids with aspartic protease enzymes of HIV-1 and plasmepsin I, were performed using AutoDock 4.2. Nelfinavir and KNI-10006 were used as the standards for HIV-1 protease and plasmepsin I, respectively. The four triterpenoids are able to interact with both enzymes. Ganoderat acid-B showed the best affinity to HIV-1 protease (binding energy= -7.49 kcal/mol and Ki= 0.001 mM) which is better than nelfinavir. Furthermore, the best affinity to Plasmepsin I is showed by ganodermanondiol (binding energy= -7.14 kcal/mol and Ki= 0.005 mM which is better than KNI-10006. According to the values of binding energy and inhibition constant, triterpenoids of G. lucidum could be developed further as both anti-HIV and anti-malaria.

The Pharmacological Effects of Triterpenoids from <i>Ganoderma lucidum</i> and the Regulation of Its Biosynthesis

“…They found that those compounds had strong inhibitory activity against HIV-1 proteases. Recently, Kang, Mutakin [29] also indicated that ganoderic acid B possessed the highest inhibiting activity to HIV-protease of four tested triterpenoids. In addition, Zhang, Ip [30] reported the extractive of G. lucidum could inhibit HIV-1 reverse transcriptase.…”

Traditional uses, chemical components and pharmacological activities of the genus Ganoderma P. Karst.: a review

“…Ganoderiol F (142), ganodermanontriol (322), ganolucidic acid A (38), ganolucidic acid B (39), ganoderic acid GS-2 (84), 15a-acetoxy-3a-hydroxylanosta-8,24-dien-26-oic acid (445), colossolactone V (297) and ganoderiol F (142) have anti-HIV-1 activity. [102][103][104][105] The hydroxyl groups at positions C-3, C-24 and C-25 in lanostane triterpenoids are the necessary active groups for anti-HIV-1 virus. 106 Among them, compounds 84 and 142 inhibit human immunodeciency virus-1 protease with IC 50 values of 20-40 mM.…”

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“…The docking results of Ganomycin 1 and Ganomycin 2 with HIV 1 protease show significant inhibitory action of these compounds, indicating the possibility that they can be used in the antiretroviral therapy as potent drugs. A triterpenoid isolated from the stem of Ganoderma sinense showed higher affinity towards HIV-1 protease with binding energy of -11.4kcal/mol using AutoDock 4.2 software 13 . Similar effect of ganoderic acid B was studied by Akbar and Yam on HIV 1 protease and indicated a huge potential for HIV treatment 14 .…”