Homology Modeling, Molecular Docking, Molecular Dynamic Simulation, and Drug-Likeness of the Modified Alpha-Mangostin against the β-Tubulin Protein of Acanthamoeba Keratitis

Abstract

Acanthamoeba species are capable of causing amoebic keratitis (AK). As a monotherapy, alpha-mangostin is effective for the treatment of AK; however, its bioavailability is quite poor. Moreover, the efficacy of therapy is contingent on the parasite and virulent strains. To improve readiness against AK, it is necessary to find other derivatives with accurate target identification. Beta-tubulin (BT) has been used as a target for anti-Acanthamoeba (A. keratitis). In this work, therefore, a model of the BT protein of A. keratitis was constructed by homology modeling utilizing the amino acid sequence from NCBI (GenBank: JQ417907.1). Ramachandran Plot was responsible for validating the protein PDB. The verified BT PDB was used for docking with the specified ligand. Based on an improved docking score compared to alpha-mangostin (AM), two modified compounds were identified: 1,6-dihydroxy-7-methoxy-2,8-bis(3-methylbut-2-en-1-yl)-9H-xanthen-9-one (C1) and 1,6-dihydroxy-2,8-bis(3-methylbut-2-en-1-yl)-9H-xanthen-9-one (C2). In addition, molecular dynamics simulations were conducted to analyze the interaction characteristics of the two bound BT–new compound complexes. During simulations, the TRP9, ARG50, VAL52, and GLN122 residues of BT-C1 that align to the identical residues in BT-AM generate consistent hydrogen bond interactions with 0–3 and 0–2. However, the BT-C2 complex has a different binding site, TYR 258, ILE 281, and SER 302, and can form more hydrogen bonds in the range 0–4. Therefore, this study reveals that C1 and C2 inhibit BT as an additive or synergistic effect; however, further in vitro and in vivo studies are needed.

Alpha-glucosidase inhibitory activities of astilbin contained in Bauhinia strychnifolia Craib. stems: an investigation by in silico and in vitro studies

“…The difference in energy between HOMO and LUMO is correlated to the chemical stability of molecules [ 44 ]. Less stable molecules possess a small HOMO–LUMO energy gap, while more stable compounds possess a large HOMO–LUMO energy gap [ 45 ]. The overall energy gap between HOMO and LUMO is depicted in Fig.…”

Curcumin analogues exert potent inhibition on human and rat gonadal 3β-hydroxysteroid dehydrogenases as potential therapeutic agents: structure-activity relationship and in silico docking

“…3D AlphaFold2-generated models included AF-P26439-F-model_v4 ( h 3β-HSD2) with 94.7% of Average pLDDT credibility and AF-P22071-F1-model_v4 ( r 3β-HSD1) with 94.66% credibility. The protein structures of h 3β-HSD2 and r 3β-HSD1 were optimised as previously described 22 , 23 . ProCheck software was used to verify the anticipated 3D structures by creating the Ramachandran plot 23 .…”

“…The protein structures of h 3β-HSD2 and r 3β-HSD1 were optimised as previously described 22 , 23 . ProCheck software was used to verify the anticipated 3D structures by creating the Ramachandran plot 23 . These protein models were docked with each chemical by Autodock 4.0 (Scripps Research Institute, http://autodock.scripps.edu ) using a genetic algorithm with local search, and a ranking clustering method for selection and the configuration of the ligand with the lowest binding energy (LBE).…”

Insights into the inhibitory activities of neolignans and diarylnonanoid derivatives from nutmeg ( Myristica fragrans Houtt.) seeds on soluble epoxide hydrolase using in vitro and in silico approaches

“…Except for compound 24 , all active compounds do not act as substrates for P-glycoprotein. This implies that the effectiveness of these compounds is unlikely to be influenced by P-glycoprotein over-expression 54 . Furthermore, compounds 19 and 20 were predicted to exhibit high absorption in the gastrointestinal (GI) tract, whereas compounds 21 – 24 were predicted to show low absorption in the GI tract.…”