VIRTUAL TARGET CONSTRUCTION FOR STRUCTURE-BASED SCREENING IN THE DISCOVERY OF HISTAMINE H2 RECEPTOR LIGANDS
Keywords:Histamine H2, Ranitidine, Homology modeling, Molecular docking, Molecular dynamics
Objective: This study aimed to develop validated targets to be employed in structure-based virtual screening (SBVS) to discover ligands for the human histamine H2 receptor (hHRH2).
Methods: The virtual targets construction was initiated by homology modeling with the reference compound ranitidine as the ligand followed by 100 ns molecular dynamics (MD) simulations. During MD simulations, the snapshot with the lowest value of the free energy of binding was selected for further validation by re-docking simulations. All simulations were performed in YASARA-Structure.
Results: The research presented here resulted in one validated target for the SBVS. Additionally, by employing a clustering module in MD simulations analysis in YASARA-Structure, more than ten different virtual targets are also available for further uses.
Conclusion: The virtual targets resulted in this research offer possibilities to construct valid SBVS protocols to identify ligands for the hHRH2.
E Tiligada, M Ennis. Histamine pharmacology: from Sir Henry Dale to the 21st century. Br J Pharmacol 2020;177:1–21.
ML Schubert, JF Rehfeld. Gastric peptides-gastrin and somatostatin. Compr Physiol 2020;10:1–32.
A Lanas, FKL Chan. Peptic ulcer disease. Lancet 2017;390:1–12.
G Nugraha, EP Istyastono. Pembuatan protokol penapisan virtual berbasis stuktur (PVBS) untuk identifikasi ligan inhibitor reseptor platelet-activating factor (PAF-r) sebagai target terapeutik ssma menggunakan YASARA. J Ris Kim 2020;11:35–42.
CN Cavasotto, AJW Orry. Ligand docking and virtual screening in structure-based drug discovery. Curr Top Med Chem 2007;7:1006–14.
A Hinchliffe. Molecular modelling for beginners. 2nd John Wiley and Sons Ltd, Weinheim, Germany; 2008. https://doi.org/10.1365/s10337-009-1412-5.
L Tan, H Geppert, MT Sisay, M Gütschow, J Bajorath. Integrating structure-and ligand-based virtual screening: comparison of individual, parallel, and fused molecular docking and similarity search calculations on multiple targets. Chem Med Chem 2008;3:1–6.
RT Kroemer. Structure-based drug design: docking and scoring. Curr Protein Pept Sci 2007;8:1–18.
AR Leach, BK Shoichet, CE Peishoff. Docking and scoring. Am Chem Soc 2006;49:1–5.
E Krieger, G Koraimann, G Vriend. Increasing the precision of comparative models with YASARA NOVA-a self-parameterizing force field. Proteins Struct Funct Genet 2002;47:1–10.
T Shimamura, M Shiroishi, S Weyand, H Tsujimoto, G Winter, V Katritch, et al. structure of the human histamine H1 receptor complex with doxepin. Nature 2011;475:1–8.
DT Jones. Protein secondary structure prediction based on position-specific scoring matrices. J Mol Biol 1999;292:1–8.
T Lengauer, M Rarey. Computational methods for biomolecular docking. Curr Opin Struct Biol 1996;6:1–5.
N Shin, E Coates, NJ Murgolo, KL Morse, M Bayne, CD Strader, et al. Molecular modeling and site-specific mutagenesis of the histamine-binding site of the histamine H4 receptor. Mol Pharmacol 2002;62:1–10.
K Liu, E Watanabe, H Kokubo. Exploring the stability of ligand binding modes to proteins by molecular dynamics simulations. J Comput Aided Mol Des 2017;31:1–10.
G Schneider. De novo molecular design, Wiley-VCH Verlag GmbH and Co., Weinheim, Germany; 2014.
EP Istyastono. Construction, validation and application of structure‐based virtual screening protocols to discover new cyclooxygenase‐2 inhibitors. Indo J Chem 2012;12:1–5.
G Marcou, D Rognan. Optimizing fragment and scaffold docking by use of molecular interaction fingerprints. J Chem Inf Model 2007;47:1–13.