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Studi Dinamika Molekul Stabilisasi Metaloproteinase Matriks 9 oleh Asam Kafeat: Molecular Dynamics Studies of Matrix Metalloprotenase-9 Stabilization by Caffeic Acid Istyastono, Enade Perdana
Jurnal Farmasi Galenika (Galenika Journal of Pharmacy) (e-Journal) Vol. 6 No. 2 (2020): (October 2020)
Publisher : Universitas Tadulako

Show Abstract | Download Original | Original Source | Check in Google Scholar | DOI: 10.22487/j24428744.2020.v6.i2.15131

Caffeic acid, a cathecol-containing phytochemical found in coffee, has been reported as a potent matrix metalloproteinase 9 (MMP9) inhibitor. The IC50 value of caffeic acid as MMP9 inhibitor could reach below 20 nM. The research presented in this article employed molecular dynamics simulations to unravel the atomic mechanism of the MMP9 inhibition by caffeic acid. Molecular dynamics simulations of MMP9 for 10 ns using YASARA-Structure were performed with and without caffeic acid as the studied ligand. The results showed that caffeic acid stabilized the stucture of the MMP9.

Identification of Interactions of ABT-341 to Dipeptidyl Peptidase IV during Molecular Dynamics Simulations: Identikasi Interaksi-interaksi ABT-341 dengan Dipeptidil Peptidase IV pada Simulasi Dinamika Molekul Istyastono, Enade; Gani, Michael
Jurnal Farmasi Galenika (Galenika Journal of Pharmacy) (e-Journal) Vol. 7 No. 2 (2021): (October 2021)
Publisher : Universitas Tadulako

Show Abstract | Download Original | Original Source | Check in Google Scholar | DOI: 10.22487/j24428744.2021.v7.i2.15516

Background: Dipeptidyl Peptidase IV (DPP-IV) is an established drug discovery target for type 2 diabetes mellitus (T2DM) therapy. On the other hand, molecular dynamics (MD) simulations have been widely employed to obtain insights of the protein-ligand interactions in structure-based drug design research projects. Moreover, a software to identify protein-ligand interactions called PyPLIF HIPPOS was made publicly available recently. Employing PyPLIF HIPPOS to identify the interactions of DPP-IV and its ligand ABT-341 during MD simulations was then of considerable interest. Objectives: The main aim of this study was to identify protein-ligand interactions of ABT-341 to DPP-IV during MD simulations. Material and Methods: The crystal structure of DPP-IV co-crystallized with ABT-341 obtained from the Protein Data Bank with code of 2I78 was used as the main material. YASARA-Structure was employed for performing 10 ns prodution run MD simulations with snapshots in every 100 ps and PyPLIF HIPPOS was used to identify the protein-ligand interactions. Results: There were 23 interactions involving 13 residues identified by employing PyPLIF HIPPOS during the MD simulations. Two of them identified in all snapshots, i.e., hydrophobic interactions to PHE357 and TYR666. Conclusions: PyPLIF HIPPOS was succesfully employed to identify the interactions of ABT-341 to DPP-IV during MD simulations.

Molecular Docking Study of Caffeic Acid as Acetylcholinesterase Inhibitor Wira Waskitha, Stephanus Satria; Istyastono, Enade Perdana; Octa Riswanto , Florentinus Dika
Journal of Food and Pharmaceutical Sciences Vol 11, No 3 (2023): J.Food.Pharm.Sci
Publisher : Integrated Research and Testing Laboratory (LPPT) Universitas Gadjah Mada

Show Abstract | Download Original | Original Source | Check in Google Scholar | DOI: 10.22146/jfps.7665

Abstract: Acetylcholinesterase (AChE) receptor is a receptor that has been widely used as a potential drug target for Alzheimer's disease. Caffeic acid is a phenolic compound that had been experimentally proven to be an inhibitor of AChE. In this study, 100 molecular docking simulations were performed to study the interaction of caffeic acid in inhibiting AChE. The molecular docking simulations were performed using YASARA software with an in-house developed plug-in. Redocking results showed that there were 99 out of 100 docking poses had an RMSD value of ≤ 2.000 Å, which indicated that the molecular docking procedure could be used for further processes. The molecular docking of caffeic acid showed that all docking poses had an RMSD value of ≤ 2.000 Å relative to the best pose of the first simulation, revealing that there was only one dominant docking pose in the AChE active site. Caffeic acid interacted favorably in the AChE active site with binding energy of about -8.022 kcal/mol. Its interactions were stabilized by hydrophobic and pi-anion interactions, in which some of the interactions resemble the same interaction of the native ligand. Keywords: Acetylcholinesterase, Alzheimer's disease, caffeic acid, molecular docking

Computational Studies of Donepezil and Acetylcholinesterase Dynamics Interactions Windah, Axl Laurens Lukas; Istyastono, Enade Perdana
Jurnal Farmasi Sains dan Komunitas (Journal of Pharmaceutical Sciences and Community) Vol 21, No 1 (2024)
Publisher : Sanata Dharma University

Show Abstract | Download Original | Original Source | Check in Google Scholar | DOI: 10.24071/jpsc.006967

Donepezil is an acetylcholinesterase (AChE) inhibitor commonly used as an anti-dementia medication for patients with Alzheimer's Disease. This research aims to determine the stability of each enantiomer R and S of donepezil as an AChE inhibitor using molecular dynamics (MD) simulations. The MD simulations were performed on a Cloud Protein Simulator (CPS) with YASARA-Structure as the main software and PyPLIF HIPPOS as the software to identify protein-ligand interactions. The MD simulations were performed in three replications of 50 ns for each enantiomer complexed to AChE. The stabilities of the AChE-donepezil complexes were analyzed by assessing the root-mean-squared deviation (RMSD) values of the AChE backbone atoms (RMSDBb) and the ligand (RMSDLigMov) during the last 5 ns of simulation time. The dynamics of the protein-ligand interactions were also analyzed during the last 5 ns. The results of these MD simulations indicate that the S-donepezil serves as a better AChE inhibitor compared to the R-donepezil.

Molecular Dynamics Simulations of Ethyl-4-[(α-L-rhamnosyloxy)-benzyl]carbamate from Moringa oleifera Lam. as a Dipeptidyl Peptidase-4 Inhibitor Dewi, I Gusti Ayu Intan Puspita; Istyastono, Enade Perdana
Jurnal Farmasi Sains dan Komunitas (Journal of Pharmaceutical Sciences and Community) Vol 22, No 2 (2025)
Publisher : Sanata Dharma University

Show Abstract | Download Original | Original Source | Check in Google Scholar | DOI: 10.24071/jpsc.009791

Diabetes mellitus is a global health problem that requires innovative solutions. Ethyl-4-[(α-L-rhamnosyloxy)-benzyl]carbamate (ERBC) compound contained in Moringa oleifera Lam. showed potential as a potent dipeptidyl peptidase-4 (DPP4) inhibitor, with an IC50 value of 0.798 µM. Molecular dynamics simulations indicated that ERBC interacts specifically with the active site of DPP4, providing a mechanistic basis for its inhibitory activity. The research utilized the latest technique developed by previously published plug-ins. The molecular docking simulations were performed 100 times. Then, the poses were clustered to sample the probable poses which were then subjected as the inputs in molecular dynamics simulations. Molecular dynamics simulations have shown that the ERBC compound interacts with the DPP4 protein at two possible poses. PyPLIF HIPPOS analysis demonstrated that ERBC, during its second replication, interacts with Glu205 and Glu206, two key amino acids involved in DPP4 activity.

Caffeine and Caffeic Acid as Acetylcholinesterase Inhibitors: In Silico Perspectives Wira Waskitha, Stephanus Satria; Wiranata, Bonifacius Ivan; Mark, Julyus Jason; Krisantia, Herluin Sekar; Kristina, Natalia; Ardine, Glory Ivana; Prasetyo, Chrisologus Ivan; Gani, Michael Raharja; Riswanto, Florentinus Dika Octa; Istyastono, Enade Perdana
Jurnal Farmasi Sains dan Komunitas (Journal of Pharmaceutical Sciences and Community) Vol 22, No 2 (2025)
Publisher : Sanata Dharma University

Show Abstract | Download Original | Original Source | Check in Google Scholar | DOI: 10.24071/jpsc.009687

Alzheimer's disease (AD) has been recognized as a significant issue affecting population health globally and tended to increase over the years. The utilization of natural products for AD treatments has been widely studied, which possibly offers better outcomes with minimum side effects. Coffee consumption has been subjected as a lifestyle propensity, which offers beneficial advantages including reducing the risk of AD. Bioactive natural compounds contained in coffee such as caffeine and caffeic acid have been experimentally proven to be acetylcholinesterase (AChE) inhibitors, a pivotal target enzyme for AD treatments. This research aimed to explore the dynamics interactions of caffeine and caffeic acid in the AChE active site using the in silico approach. In this study, 100 redocking and docking simulations were implemented before the molecular dynamics (MD) simulations. The 55-ns MD simulations of huprine X, caffeine, and caffeic acid were implemented to study the dynamics interactions. Conformational stability, free energies of binding, and interaction hotspots were identified during the simulations. Our findings informed that caffeine interacted in the active site during the simulations, revealing the importance of the imidazole ring in maintaining the interactions. In contrast, caffeic acid interacted longer in the plausible allosteric site, forming ionic, hydrogen bonds, and aromatic interactions.

A Structure-Based Virtual Screening Protocol Utilizing PyPLIF HIPPOS and Vina for Targeting BACE-1 Primana, Mala Hikmawan; Oka, Mitsue; Istyastono, Enade Perdana; Riswanto, Florentinus Dika Octa
Journal of Food and Pharmaceutical Sciences Vol 13, No 4 (2025): J.Food.Pharm.Sci
Publisher : Integrated Research and Testing Laboratory (LPPT) Universitas Gadjah Mada

Show Abstract | Download Original | Original Source | Check in Google Scholar | DOI: 10.22146/jfps.24790

Alzheimer’s Disease (AD) is a leading cause of dementia, characterized by progressive cognitive decline driven in part by amyloid-β (Aβ) accumulation. The β-site amyloid precursor protein cleaving enzyme 1 (BACE-1) is responsible for initiating Aβ generation, making it a central therapeutic target. Yet, developing effective BACE-1 inhibitors has proven difficult due to structural complexity and pharmacological limitation. This study aimed to construct and validate a structure-based virtual screening (SBVS) workflow combining Vina and PyPLIF HIPPOS to facilitate the identification of promising BACE-1 ligands. The protocol was validated through 100 independent redocking experiments of the native ligand (PDB ID: 3L5F), all reproducing the crystallographic pose with RMSD < 2.0 Å. Large-scale screening of the DUDE dataset (283 active ligands; 18,100 decoys) generated interaction fingerprint, which were subsequently analyzed using Recursive Partitioning and Regression Trees (RPART) under varying prior probabilities. At the optimal prior ratio of 0.82:0.18, the model achieved an enrichment factor (EF) of 10.03, surpassing the DUDE benchmark (EF = 8.1). analysis consistently highlighted ionic interactions with Asp289 and hydrophobic contacts with Trp137 as key determinants of ligand activity. From 283 active ligands, 32 were classified as true positives, narrowing the pool of candidates and interpretable SBVS protocol and proposing a dual anchoring strategy involving Asp289 and Trp137 as a rational design principle for novel BACE-1 inhibitors in AD therapy.

A Structure-Based Virtual Screening Protocol Utilizing PyPLIF HIPPOS and Vina for Targeting BACE-1 Primana, Mala Hikmawan; Oka, Mitsue; Istyastono, Enade Perdana; Riswanto, Florentinus Dika Octa
Journal of Food and Pharmaceutical Sciences Vol 13, No 4 (2025): J.Food.Pharm.Sci
Publisher : Integrated Research and Testing Laboratory (LPPT) Universitas Gadjah Mada

Show Abstract | Download Original | Original Source | Check in Google Scholar | DOI: 10.22146/jfps.24790

Alzheimer’s Disease (AD) is a leading cause of dementia, characterized by progressive cognitive decline driven in part by amyloid-β (Aβ) accumulation. The β-site amyloid precursor protein cleaving enzyme 1 (BACE-1) is responsible for initiating Aβ generation, making it a central therapeutic target. Yet, developing effective BACE-1 inhibitors has proven difficult due to structural complexity and pharmacological limitation. This study aimed to construct and validate a structure-based virtual screening (SBVS) workflow combining Vina and PyPLIF HIPPOS to facilitate the identification of promising BACE-1 ligands. The protocol was validated through 100 independent redocking experiments of the native ligand (PDB ID: 3L5F), all reproducing the crystallographic pose with RMSD < 2.0 Å. Large-scale screening of the DUDE dataset (283 active ligands; 18,100 decoys) generated interaction fingerprint, which were subsequently analyzed using Recursive Partitioning and Regression Trees (RPART) under varying prior probabilities. At the optimal prior ratio of 0.82:0.18, the model achieved an enrichment factor (EF) of 10.03, surpassing the DUDE benchmark (EF = 8.1). analysis consistently highlighted ionic interactions with Asp289 and hydrophobic contacts with Trp137 as key determinants of ligand activity. From 283 active ligands, 32 were classified as true positives, narrowing the pool of candidates and interpretable SBVS protocol and proposing a dual anchoring strategy involving Asp289 and Trp137 as a rational design principle for novel BACE-1 inhibitors in AD therapy.

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