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Article ; Online: Pharmacophore Modeling, Docking, and Molecular Dynamics Simulation of Flavonoids as Inhibitors of Urokinase-type Plasminogen Activator

Daryono Hadi Tjahjono / Bina Lohita Sari / Slamet Ibrahim

Journal of Mathematical and Fundamental Sciences, Vol 53, Iss

2022 Volume 3

Abstract: The urokinase-type plasminogen activator (uPA) system plays a significant role in the invasion and metastasis of cancer cells. The present study was conducted to investigate natural product compounds as inhibitors and hit molecules of uPA using in-silico ...

Abstract	The urokinase-type plasminogen activator (uPA) system plays a significant role in the invasion and metastasis of cancer cells. The present study was conducted to investigate natural product compounds as inhibitors and hit molecules of uPA using in-silico analysis. A pharmacophore model was built to screen the Indonesian Herbal Database (HerbalDB) to obtain inhibitors of different scaffolds. Based on the molecular docking score, four ligands were selected as potential uPA inhibitors. Subsequently, the stability of the ligand-uPA complex was analyzed using molecular dynamics (MD) simulation. An RMSD graph of the backbone protein and the RMSF values of the amino acid residues were also determined. In addition, the MM-PBSA method was applied to calculate the free binding energy. According to the results, Model_3, characterized by aromatic rings 23 (F1 and F2), cationic H-bond donor (F3), and metal ligator (F4) features, had an adequate goodness-of-hit score (GH). The four top-ranked ligands, isorhamnetin, rhamnetin, quercetin, and kaempferol, showed higher docking scores compared to the others. This study confirmed that isorhamnetin, rhamnetin, and kaempferol build stable complexes with uPA with lower binding energy than quercetin.
Keywords	anti-cancer ; flavonoids ; in-silico study ; isorhamnetin ; kaempferol ; quercetin ; Science ; Q ; Science (General) ; Q1-390
Subject code	540
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	ITB Journal Publisher
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Cyclin-Dependent Kinase 4 and 6 Inhibitors in Cell Cycle Dysregulation for Breast Cancer Treatment

Ni Made Pitri Susanti / Daryono Hadi Tjahjono

Molecules, Vol 26, Iss 4462, p

2021 Volume 4462

Abstract: In cell development, the cell cycle is crucial, and the cycle progression’s main controllers are endogenous CDK inhibitors, cyclin-dependent kinases (CDKs), and cyclins. In response to the mitogenic signal, cyclin D is produced and retinoblastoma protein ...

Abstract	In cell development, the cell cycle is crucial, and the cycle progression’s main controllers are endogenous CDK inhibitors, cyclin-dependent kinases (CDKs), and cyclins. In response to the mitogenic signal, cyclin D is produced and retinoblastoma protein (Rb) is phosphorylated due to activated CDK4/CDK6. This causes various proteins required in the cell cycle progression to be generated. In addition, complexes of CDK1-cyclin A/B, CDK2-cyclin E/A, and CDK4/CDK6-cyclin D are required in each phase of this progression. Cell cycle dysregulation has the ability to lead to cancer. Based on its role in the cell cycle, CDK has become a natural target of anticancer therapy. Therefore, understanding the CDK structures and the complex formed with the drug, helps to foster the development of CDK inhibitors. This development starts from non-selective CDK inhibitors to selective CDK4/CDK6 inhibitors, and these have been applied in clinical cancer treatment. However, these inhibitors currently require further development for various hematologic malignancies and solid tumors, based on the results demonstrated. In drug development, the main strategy is primarily to prevent and asphyxiate drug resistance, thus a determination of specific biomarkers is required to increase the therapy’s effectiveness as well as patient selection suitability in order to avoid therapy failure. This review is expected to serve as a reference for early and advanced-stage researchers in designing new molecules or repurposing existing molecules as CDK4/CDK6 inhibitors to treat breast cancer.
Keywords	cell cycle ; CDK ; cancer ; CDK inhibitors ; Organic chemistry ; QD241-441
Subject code	616
Language	English
Publishing date	2021-07-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Structural Insight and Development of EGFR Tyrosine Kinase Inhibitors

Tasia Amelia / Rahmana Emran Kartasasmita / Tomohiko Ohwada / Daryono Hadi Tjahjono

Molecules, Vol 27, Iss 819, p

2022 Volume 819

Abstract: Lung cancer has a high prevalence, with a growing number of new cases and mortality every year. Furthermore, the survival rate of patients with non-small-cell lung carcinoma (NSCLC) is still quite low in the majority of cases. Despite the use of ... ...

Abstract	Lung cancer has a high prevalence, with a growing number of new cases and mortality every year. Furthermore, the survival rate of patients with non-small-cell lung carcinoma (NSCLC) is still quite low in the majority of cases. Despite the use of conventional therapy such as tyrosine kinase inhibitor for Epidermal Growth Factor Receptor (EGFR), which is highly expressed in most NSCLC cases, there was still no substantial improvement in patient survival. This is due to the drug’s ineffectiveness and high rate of resistance among individuals with mutant EGFR. Therefore, the development of new inhibitors is urgently needed. Understanding the EGFR structure, including its kinase domain and other parts of the protein, and its activation mechanism can accelerate the discovery of novel compounds targeting this protein. This study described the structure of the extracellular, transmembrane, and intracellular domains of EGFR. This was carried out along with identifying the binding pose of commercially available inhibitors in the ATP-binding and allosteric sites, thereby clarifying the research gaps that can be filled. The binding mechanism of inhibitors that have been used clinically was also explained, thereby aiding the structure-based development of new drugs.
Keywords	activation ; binding ; EGFR ; inhibitor ; kinase ; Organic chemistry ; QD241-441
Subject code	616
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Identification of Phosphatidylinositol 3-kinase δ (PI3Kδ) Inhibitor

Muhammad Arba / Malindo Sufriadin / Daryono Hadi Tjahjono

Indonesian Journal of Chemistry, Vol 20, Iss 5, Pp 1070-

Pharmacophore-based Virtual Screening and Molecular Dynamics Simulation

2020 Volume 1079

Abstract: Phosphatidylinositol 3-kinase δ (PI3Kδ) is a validated drug target for the treatment of cancer. The present study aims to search for new inhibitors of PI3Kδ by employing pharmacophore modelling using LigandScout Advanced 4.3 software. The three hydrogen ... ...

Abstract	Phosphatidylinositol 3-kinase δ (PI3Kδ) is a validated drug target for the treatment of cancer. The present study aims to search for new inhibitors of PI3Kδ by employing pharmacophore modelling using LigandScout Advanced 4.3 software. The three hydrogen bond acceptors and two hydrophobic features were proposed as a pharmacophore model using LASW1976 structure. The model was then validated using the Area Under Curve (AUC) of Receiver Operating Characteristic (ROC) and GH score. It was used to screen new molecules in the ZINC database, which resulted in 599 hits. All 599 hits were then docked into PI3Kδ protein, and five best hits were submitted to 50 ns molecular dynamics simulations. Each hit complexed with PI3Kδ underwent minor conformational changes as indicated by the values of Root Mean Square Deviation (RMSD) and Root Mean Square Fluctuation (RMSF). Furthermore, prediction of the binding free energy using Molecular Mechanics-Poisson Boltzmann Surface Area (MM-PBSA) method showed that five hits, i.e., Lig25/ZINC253496376, Lig682/ZINC98047241, Lig449/ZINC85878047, Lig554/ZINC253389510, and Lig199/ZINC12638303, had lower binding energy compared to LASW1976. This result indicated their potentials as new inhibitors of PI3Kδ.
Keywords	pi3k ; molecular docking ; pharmacophore modeling ; molecular dynamics simulation ; Chemistry ; QD1-999
Subject code	540 ; 541
Language	English
Publishing date	2020-07-01T00:00:00Z
Publisher	Department of Chemistry, Universitas Gadjah Mada
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Ligand-Based Pharmacophore Modeling, Molecular Docking, and Molecular Dynamic Studies of Dual Tyrosine Kinase Inhibitor of EGFR and VEGFR2

Frangky Sangande / Elin Julianti / Daryono Hadi Tjahjono

International Journal of Molecular Sciences, Vol 21, Iss 7779, p

2020 Volume 7779

Abstract: Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR2) play an important role in cancer growth. Both of them have close relationships. Expression of EGFR will induce an angiogenic factor (VEGF) release for ... ...

Abstract	Epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor 2 (VEGFR2) play an important role in cancer growth. Both of them have close relationships. Expression of EGFR will induce an angiogenic factor (VEGF) release for binding with VEGFR2. However, the existence of VEGF up-regulation independent of EGFR leads to cancer cell resistance to anti-EGFR. Therefore, a therapeutic approach targeting EGFR and VEGFR2 simultaneously may improve the outcome of cancer treatment. The present study was designed to identify potential compounds as a dual inhibitor of EGFR and VEGFR2 by the computational method. Firstly, the ligand-based pharmacophore model for each target was setup to screen of ZINC database of purchasable compounds. The hit compounds obtained by pharmacophore screening were then further screened by molecular docking studies. Taking erlotinib (EGFR inhibitor) and axitinib (VEGFR2 inhibitor) as reference drugs, six potential compounds (ZINC08398597, ZINC12047553, ZINC16525481, ZINC17418102, ZINC21942954, and ZINC38484632) were selected based on their docking scores and binding interaction. However, molecular dynamics simulations demonstrated that only ZINC16525481 and ZINC38484632 which have good binding free energy and stable hydrogen bonding interactions with EGFR and VEGFR2. The result represents a promising starting point for developing potent dual tyrosine kinases inhibitor of EGFR and VEGFR2.
Keywords	dual inhibitor ; EGFR ; VEGFR2 ; ligand-based pharmacophore ; molecular docking ; molecular dynamics ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	540
Language	English
Publishing date	2020-10-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A Search for Cyclin-Dependent Kinase 4/6 Inhibitors by Pharmacophore-Based Virtual Screening, Molecular Docking, and Molecular Dynamic Simulations

Ni Made Pitri Susanti / Sophi Damayanti / Rahmana Emran Kartasasmita / Daryono Hadi Tjahjono

International Journal of Molecular Sciences, Vol 22, Iss 13423, p

2021 Volume 13423

Abstract: The G1 phase of cell cycle progression is regulated by Cyclin-Dependent Kinase 4 (CDK4) as well as Cyclin-Dependent Kinase 6 (CDK6), and the acivities of these enzymes are regulated by the catalytic subunit, cyclin D. Cell cycle control through selective ...

Abstract	The G1 phase of cell cycle progression is regulated by Cyclin-Dependent Kinase 4 (CDK4) as well as Cyclin-Dependent Kinase 6 (CDK6), and the acivities of these enzymes are regulated by the catalytic subunit, cyclin D. Cell cycle control through selective pharmacological inhibition of CDK4/6 has proven to be beneficial in the treatment of estrogen receptor-positive (ER-positive) breast cancer, particularly improving the progression-free survival of patients. Thus, targeting specific inhibition on CDK4/6 is bound to increase therapeutic efficiency. This study aimed to obtain CDK4/6 inhibitors through a pharmacophore-based virtual screening of the ZINC15 purchasable compound database using the in silico method. The pharmacophore model was designed based on the FDA-approved cdk4/6 inhibitor structures, and molecular docking was performed to further screen the hit compounds obtained. A total of eight compounds were selected based on docking results and interactions with CDK4 and CDK6, using palbociclib as the reference drug. According to the results, the compounds of ZINC585292724 and ZINC585291674 were the best compounds based on free binding energy, as well as hydrogen bond stability, and, therefore, exhibit potential as starting points in the development of CDK4/6 inhibitors.
Keywords	CDK4 ; CDK6 ; cell cycle ; pharmacophore ; virtual screening ; molecular docking ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	540
Language	English
Publishing date	2021-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Molecular Dynamics of Cobalt Protoporphyrin Antagonism of the Cancer Suppressor REV-ERBβ

Taufik Muhammad Fakih / Fransiska Kurniawan / Muhammad Yusuf / Mudasir Mudasir / Daryono Hadi Tjahjono

Molecules, Vol 26, Iss 3251, p

2021 Volume 3251

Abstract: Nuclear receptor REV-ERBβ is an overexpressed oncoprotein that has been used as a target for cancer treatment. The metal-complex nature of its ligand, iron protoporphyrin IX (Heme), enables the REV-ERBβ to be used for multiple therapeutic modalities as a ...

Abstract	Nuclear receptor REV-ERBβ is an overexpressed oncoprotein that has been used as a target for cancer treatment. The metal-complex nature of its ligand, iron protoporphyrin IX (Heme), enables the REV-ERBβ to be used for multiple therapeutic modalities as a photonuclease, a photosensitizer, or a fluorescence imaging agent. The replacement of iron with cobalt as the metal center of protoporphyrin IX changes the ligand from an agonist to an antagonist of REV-ERBβ. The mechanism behind that phenomenon is still unclear, despite the availability of crystal structures of REV-ERBβ in complex with Heme and cobalt protoporphyrin IX (CoPP). This study used molecular dynamic simulations to compare the effects of REV-ERBβ binding to Heme and CoPP, respectively. The initial poses of Heme and CoPP in complex with agonist and antagonist forms of REV-ERBβ were predicted using molecular docking. The binding energies of each ligand were calculated using the MM/PBSA method. The computed binding affinity of Heme to REV-ERBβ was stronger than that of CoPP, in agreement with experimental results. CoPP altered the conformation of the ligand-binding site of REV-ERBβ, disrupting the binding site for nuclear receptor corepressor, which is required for REV-ERBβ to regulate the transcription of downstream target genes. Those results suggest that a subtle change in the metal center of porphyrin can change the behavior of porphyrin in cancer cell signaling. Therefore, modification of porphyrin-based agents for cancer therapy should be conducted carefully to avoid triggering unfavorable effects.
Keywords	breast cancer ; REV-ERBβ ; porphyrin ; nuclear receptor corepressor (NCoR) ; molecular dynamics (MD) simulation ; Organic chemistry ; QD241-441
Subject code	500
Language	English
Publishing date	2021-05-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Alpha-mangostin, piperine and beta-sitosterol as hepatitis C antivirus (HCV)

Anjar Hermadi Saputro / Tasia Amelia / Andhika Bintang Mahardhika / Aty Widyawaruyanti / Tutik Sri Wahyuni / Adita Ayu Permanasari / Aluicia Anita Artarini / Daryono Hadi Tjahjono / Sophi Damayanti

Heliyon, Vol 9, Iss 9, Pp e20141- (2023)

In silico and in vitro studies

2023

Abstract: Hepatitis C is still a serious liver case of health. Up to now the development of anti-Hepatitis C Virus (HCV) drugs is challenging, especially the development of natural material compounds as anti-HCV. In the present study, we evaluated the probability ... ...

Abstract	Hepatitis C is still a serious liver case of health. Up to now the development of anti-Hepatitis C Virus (HCV) drugs is challenging, especially the development of natural material compounds as anti-HCV. In the present study, we evaluated the probability of α-mangostin, piperine, and β-sitosterol as anti-HCV with the in silico and in vitro approaches. Molecular docking was performed between nonstructural protein 5B (NS5B, PDB ID 3FQL) with α-mangostin, piperine, and β-sitosterol by Autodock Tools® and BIOVIA Discovery Studio®. Subsequently, molecular dynamics simulations were conducted for 200 ns, evaluating the dynamic interaction between the ligands and the viral protein NS5B. Furthermore, compound characterization at the hepatocarcinoma cell line was employed. α-Mangostin with NS5B complex demonstrated the most negative binding free energy value based on MM-PBSA calculation with a value of −9.13 kcal/mol. In vitro test showed that IC50 of α -mangostin was 2.70 ± 0.92 μM, IC50 of piperine was 52.18 ± 3.21 μM, IC50 of β-sitosterol was >100 μM. α-Mangostin can serve as a valuable lead compound for further development of the anti-HCV.
Keywords	Alpha-mangostin ; Anti-Hepatitis C ; Beta-sitosterol ; Piperine ; Science (General) ; Q1-390 ; Social sciences (General) ; H1-99
Subject code	570
Language	English
Publishing date	2023-09-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Molecular modeling on the identification of potential Janus Kinase 3 (JAK3) inhibitor based on the Indonesian Medicinal Plant Database

Muhammad Arba / Sanang Nur Safitri / Andry Nur Hidayat / Arry Yanuar / Muhammad Sulaiman Zubair / Asmiyenti Djaliasrin Djalil / Daryono Hadi Tjahjono

Journal of Mathematical and Fundamental Sciences, Vol 52, Iss

2020 Volume 3

Abstract: The Janus tyrosine kinases (JAKs) have shown great promise as therapeutic protein targets in the treatment of cancer and inflammation diseases. This study used pharmacophore modeling to identify potential inhibitors of Janus kinase 3 (JAK3). A ... ...

Abstract	The Janus tyrosine kinases (JAKs) have shown great promise as therapeutic protein targets in the treatment of cancer and inflammation diseases. This study used pharmacophore modeling to identify potential inhibitors of Janus kinase 3 (JAK3). A pharmacophore model was developed based on a known JAK3 inhibitor (1NX) and was employed to search for potential JAK3 inhibitors against Indonesian herbal compounds. Among 28 hit molecules that were identified and subjected to a molecular docking protocol against JAK3, the three compounds that had the highest affinities toward JAK3 were camelliaside B, 3-O-galloylepicatechin-(4beta-6)-epicatechin-3-O-gallate, and mesuaferrone B. These were then each subjected to a 50-ns molecular dynamics (MD) simulation. Analysis of RMSD and RMSF values indicated that the three compounds reached stability during the MD simulation. Interestingly, all three compounds had lower binding energies than 1NX against JAK3, as predicted by the MM-PBSA binding energy calculation.
Keywords	Janus kinase ; MM-PBSA ; molecular dynamics simulation ; pharmacophore modeling ; virtual screening ; Science ; Q ; Science (General) ; Q1-390
Subject code	540
Language	English
Publishing date	2020-12-01T00:00:00Z
Publisher	ITB Journal Publisher
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Insight into the Interaction of Cationic Porphyrin-Anthraquinone Hybrids with Hsp90

Muhammad Arba / Ruslin / Rahmana Emran Kartasasmita / Slamet Ibrahim Surantaatmadja / Daryono Hadi Tjahjono

Journal of Mathematical and Fundamental Sciences, Vol 50, Iss 3, Pp 303-

In Silico Analysis

2018 Volume 314

Abstract: Heat shock protein 90 (Hsp90) is responsible for the correct folding of many cellular proteins. Several Hsp90 inhibitors have been developed for cancer treatment. The present in silico study aimed to evaluate the potential of several porphyrin ... ...

Abstract	Heat shock protein 90 (Hsp90) is responsible for the correct folding of many cellular proteins. Several Hsp90 inhibitors have been developed for cancer treatment. The present in silico study aimed to evaluate the potential of several porphyrin derivatives conjugated with anthraquinone groups as Hsp90 inhibitors by using simulation of molecular docking and molecular dynamics. The binding mode of porphyrin hybrids to Hsp90, which was examined by using AutoDock 4.2, showed that all six porphyrin compounds fit well in the binding pocket of Hsp90. The pi-cationic interactions with Lys58 were exclusively observed in the interaction of each porphyrin hybrid. Stabilities of porphyrin-Hsp90 complexes were confirmed by 40-ns MD simulation, which was carried out with the help of AMBER16. Prediction of ligand affinity by using the MM-PBSA method showed that all complexes were energetically favorable as indicated by a negative binding free energy. The predicted affinities of tris−H2PyP−AQ, tris−H2PzP−AQ, bis−H2PzP−AQ, and mono−H2PzP−AQ are better than those of geldanamycin, a known inhibitor of Hsp90, which shows the importance of the electrostatic and van der Waals energies for ligand binding.
Keywords	Hsp90 ; MM-PBSA ; molecular docking ; molecular dynamics simulation ; porphyrin ; Science ; Q ; Science (General) ; Q1-390
Subject code	540
Language	English
Publishing date	2018-12-01T00:00:00Z
Publisher	ITB Journal Publisher
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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