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Pyrazolo[3,4-d]pyrimidines as novel inhibitors of O-acetyl-l-serine sulfhydrylase of Entamoeba histolytica: an in silico study

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Abstract

Amoebiasis, a worldwide explosive epidemic, caused by the gastrointestinal anaerobic protozoan parasite Entamoeba histolytica, infects the large intestine and, in advance stages, liver, kidney, brain and lung. Metronidazole (MNZ)—the first line medicament against amoebiasis—is potentially carcinogenic to humans and shows significant side-effects. Pyrazolo[3,4-d]pyrimidine compounds have been reported to demonstrate antiamoebic activity. In silico molecular docking simulations on nine pyrazolo[3,4-d]pyrimidine molecules without linkers (molecules 1–9) and nine pyrazolo[3,4-d]pyrimidine molecules with a trimethylene linker (molecules 10–18) along with the reference drug metronidazole (MNZ) were conducted using the modules of the programs Glide-SP, Glide-XP and Autodock with O-acetyl-l-serine sulfhydrylase (OASS) enzyme—a promising target for inhibiting the growth of Entamoeba histolytica. Docking simulations using Glide-SP demonstrate good agreement with reported biological activities of molecules 1–9 and indicate that molecules 2 and 4 may act as potential high affinity inhibitors. Trimethylene linker molecules show improved binding affinities among which molecules 15 and 16 supersede. MD simulations on the best docked poses of molecules 2, 4, 15, 16 and MNZ were carried out for 20 ns using DESMOND. It was observed that the docking complexes of molecules 4, 15 and MNZ remain stable in aqueous conditions and do not undergo noticeable fluctuations during the course of the dynamics. Relative binding free energy calculations of the ligands with the enzyme were executed on the best docked poses using the molecular mechanics generalized Born surface area (MM-GBSA) approach, which show good agreement with the reported biological activities.

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Acknowledgments

U. Y. is thankful to DST, New Delhi, India for financial support through SERC Fast Track Young Scientist scheme(SR/FT/CS-78/2010) and UGC, New Delhi, India for the award of a Raman Fellowship for postdoctoral studies in the United States [F.No. 5-1/2013(IC)].

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Authors and Affiliations

  1. Department of Physics, D.D.U. Gorakhpur University, Gorakhpur, 273009, India

    Umesh Yadava, Bindesh Kumar Shukla & Mihir Roychoudhury

  2. Department of Applied Physics, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Rae Bareilly Road, Lucknow, 226025, India

    Devesh Kumar

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  1. Umesh Yadava
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  2. Bindesh Kumar Shukla
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Correspondence to Umesh Yadava.

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Yadava, U., Shukla, B.K., Roychoudhury, M. et al. Pyrazolo[3,4-d]pyrimidines as novel inhibitors of O-acetyl-l-serine sulfhydrylase of Entamoeba histolytica: an in silico study. J Mol Model 21, 96 (2015). https://doi.org/10.1007/s00894-015-2631-3

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