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

Hariyanti Hariyanti; Kusmadi Kurmardi; Arry Yanuar; Hayun Hayun

doi:10.22146/ijc.54745

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

https://doi.org/10.22146/ijc.54745

Hariyanti Hariyanti⁽¹⁾, Kusmadi Kurmardi⁽²⁾, Arry Yanuar⁽³⁾, Hayun Hayun^(4*)

(1) Faculty of Pharmacy and Science, Universitas Muhammadiyah Prof. DR. HAMKA, Jl. Delima II/IV, Duren Sawit, East Jakarta 13460, Indonesia
(2) Faculty of Medicine, Universitas Indonesia, UI Salemba Campus, Jl. Salemba Raya No. 6, Central Jakarta 10430, Indonesia
(3) Faculty of Pharmacy, Universitas Indonesia, Depok 16424, West Java, Indonesia
(4) Faculty of Pharmacy, Universitas Indonesia, Depok 16424, West Java, Indonesia
(*) Corresponding Author

Abstract

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.

Keywords

asymmetric hexahydro-2H-indazole analogs of curcumin; AIACs; estrogen receptor alpha inhibitor; ERα inhibitor; pharmacophore modeling; molecular docking; breast cancer

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DOI: https://doi.org/10.22146/ijc.54745