Structure based pharmacophore modeling, virtual screening, molecular docking and ADMET approaches for identification of natural anti-cancer agents targeting XIAP protein

AbstractX-linked inhibitor of apoptosis protein (XIAP) is a member of inhibitor of apoptosis protein (IAP) family responsible for neutralizing the caspases-3, caspases-7, and caspases-9. Overexpression of the protein decreased the apoptosis process in the cell and resulting development of cancer. Different types of XIAP antagonists are generally used to repair the defective apoptosis process that can eliminate carcinoma from living bodies. The chemically synthesis compounds discovered till now as XIAP inhibitors exhibiting side effects, which is making difficulties during the treatment of chemotherapy. So, the study has design to identifying new natural compounds that are able to induce apoptosis by freeing up caspases and will be low toxic. To identify natural compound, a structure-based pharmacophore model to the protein active site cavity was generated following by virtual screening, molecular docking and molecular dynamics (MD) simulation. Initially, seven hit compounds were retrieved and based on molecular docking approach four compounds has chosen for further evaluation. To confirm stability of the selected drug candidate to the target protein the MD simulation approach were employed, which confirmed stability of the three compounds. Based on the finding, three newly obtained compounds namely Caucasicoside A (ZINC77257307), Polygalaxanthone III (ZINC247950187), and MCULE-9896837409 (ZINC107434573) may serve as lead compounds to fight against the treatment of XIAP related cancer, although further evaluation through wet lab is necessary to measure the efficacy of the compounds.

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Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking, ADMET, and Molecular Dynamics (MD) Simulation of Potential Inhibitors of PD-L1 from the Library of Marine Natural Products

Marine Drugs ◽

10.3390/md20010029 ◽

2021 ◽

Vol 20 (1) ◽

pp. 29

Author(s):

Lianxiang Luo ◽

Ai Zhong ◽

Qu Wang ◽

Tongyu Zheng

Keyword(s):

Molecular Dynamics ◽

Natural Products ◽

Molecular Docking ◽

Virtual Screening ◽

Marine Natural Products ◽

Md Simulation ◽

Pharmacophore Model ◽

Pharmacophore Modeling ◽

Dynamics Simulation ◽

Stable Conformation

Background: In the past decade, several antibodies directed against the PD-1/PD-L1 interaction have been approved. However, therapeutic antibodies also exhibit some shortcomings. Using small molecules to regulate the PD-1/PD-L1 pathway may be another way to mobilize the immune system to fight cancer. Method: 52,765 marine natural products were screened against PD-L1(PDBID: 6R3K). To identify natural compounds, a structure-based pharmacophore model was generated, following by virtual screening and molecular docking. Then, the absorption, distribution, metabolism, and excretion (ADME) test was carried out to select the most suitable compounds. Finally, molecular dynamics simulation was also performed to validate the binding property of the top compound. Results: Initially, 13 small marine molecules were screened based on the pharmacophore model. Then, two compounds were selected for further evaluation based on the molecular docking scores. After ADME and toxicity studies, molecule 51320 was selected for further verification. By molecular dynamics analysis, molecule 51320 maintains a stable conformation with the target protein, so it has the chance to become an inhibitor of PD-L1. Conclusions: Through structure-based pharmacophore modeling, virtual screening, molecular docking, ADMET approaches, and molecular dynamics (MD) simulation, the marine natural compound 51320 can be used as a small molecule inhibitor of PD-L1.

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Abstract 4548: Identify novel molecular structures targeting X-Linked Inhibitor of Apoptosis Protein by ligand-based virtual screening.

10.1158/1538-7445.am2013-4548 ◽

2013 ◽

Author(s):

Jin Wang ◽

Charles B. Duke ◽

Wei Li

Keyword(s):

Virtual Screening ◽

Molecular Structures ◽

Inhibitor Of Apoptosis ◽

Inhibitor Of Apoptosis Protein ◽

Apoptosis Protein

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Ligand Based Pharmacophore Modeling, Virtual Screening, and Molecular Docking Studies of Asymmetrical Hexahydro-2H-Indazole Analogs of Curcumin (AIACs) to Discover Novel Estrogen Receptors Alpha (ERα) Inhibitor

Indonesian Journal of Chemistry ◽

10.22146/ijc.54745 ◽

2020 ◽

Vol 21 (1) ◽

pp. 137

Author(s):

Hariyanti Hariyanti ◽

Kusmadi Kurmardi ◽

Arry Yanuar ◽

Hayun Hayun

Keyword(s):

Molecular Docking ◽

Virtual Screening ◽

Estrogen Receptor Alpha ◽

Pharmacophore Model ◽

Pharmacophore Modeling ◽

Cytotoxic Agents ◽

Breast Development ◽

Hydrogen Bond Acceptor ◽

Lipinski’S Rule ◽

Pharmacophore Models

The estrogen receptor alpha (ERα) plays an important role in breast development and pro-proliferation signal activation in the normal and cancerous breast. The ERα inhibitors were potentially active as cytotoxic agents against breast cancer. This study was conducted in order to find Asymmetrical Hexahydro-2H-Indazole Analogs of Curcumin (AIACs) as hits of ERα inhibitor. A training set of 17 selected ERα inhibitors was used to create 10 pharmacophore models using LigandScout 4.2. The pharmacophore models were validated using 383 active compounds as positive data and 20674 decoys as negative data obtained from DUD.E. Model 2 was found as the best pharmacophore model and consisted of three types of pharmacophore features, viz. one hydrophobic, one hydrogen bond acceptor, and aromatic interactions. Model 2 was utilized for ligand-based virtual screening 186 of AIACs, AMACs, intermediates, and Mannich base derivative compounds. The hits obtained were further screened using molecular docking, analyzed using drug scan, and tested for its synthesis accessibility. Fourteen compounds were fulfilled as hits in pharmacophore modeling, in which 10 hits were selected by molecular docking, but only seven hits met Lipinski’s rule of five and had medium synthesis accessibility. In conclusion, seven compounds were suggested to be potentially active as ERα inhibitors and deserve to be synthesized and further investigated.

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Virtual Screening, Molecular Docking and Pharmacophore Modeling of Phytoconstituents of Flavones as Aldose Reductase Inhibitors

Journal of Pharmaceutical Research International ◽

10.9734/jpri/2021/v33i41b32348 ◽

2021 ◽

pp. 94-107

Author(s):

Jainey P. James ◽

Asmath Maziyuna Fabin ◽

Pradija Sasidharan ◽

Pankaj Kumar

Keyword(s):

Molecular Docking ◽

Virtual Screening ◽

Aldose Reductase ◽

Pharmacophore Model ◽

Polyol Pathway ◽

Pharmacophore Modeling ◽

Antidiabetic Activity ◽

Energy Calculation ◽

Reductase Inhibitors ◽

Characteristic Features

Flavones are an important class of naturally occurring heterocycles possessing various pharmacological activities. An in silico approach was carried out where 506 compounds containing flavone ring were utilised as ligand against the target aldose reductase enzyme. Aldose reductase is the rate-limiting enzyme in the polyol pathway, which indirectly causes diabetic complications like diabetic nephropathy and diabetic retinopathy. The flavone containing compounds retrieved from the PubChem were investigated by HTVS (high throughput virtual screening) followed by molecular docking using glide SP and XP docking module in Maestro of Schrodinger software. Among them, the best fifteen compounds were selected for further studies. The binding energy calculation was done using the Prime MM-GBSA module. PASS online prediction tools were used for predicting the antidiabetic activity of the compounds. Also, a pharmacophore model was generated for best interacted fifteen compounds by Phase, which can be used for evaluation of the characteristic features essential for this specific biological activity. The ADMET properties of the compounds were determined using the Qikprop module in the Schrodinger software.

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