caa a22 4500 605512574 CHVBK 20210128100656.0 cr unu---uuuuu 210128e20150401xx s 000 0 eng 10.1007/s00894-015-2631-3 doi (NATIONALLICENCE)springer-10.1007/s00894-015-2631-3 Pyrazolo[3,4- d ]pyrimidines as novel inhibitors of O-acetyl- l -serine sulfhydrylase of Entamoeba histolytica [Elektronische Daten] an in silico study [Umesh Yadava, Bindesh Shukla, Mihir Roychoudhury, Devesh Kumar] 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 20ns 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. Springer-Verlag Berlin Heidelberg, 2015 Entamoeba histolytica nationallicence Glide docking nationallicence Schrodinger nationallicence ADME nationallicence Molecular dynamics nationallicence Yadava Umesh Department of Physics, D.D.U. Gorakhpur University, 273009, Gorakhpur, India aut Shukla Bindesh Department of Physics, D.D.U. Gorakhpur University, 273009, Gorakhpur, India aut Roychoudhury Mihir Department of Physics, D.D.U. Gorakhpur University, 273009, Gorakhpur, India aut Kumar Devesh Department of Applied Physics, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Rae Bareilly Road, 226025, Lucknow, India aut Journal of Molecular Modeling Springer Berlin Heidelberg 21/4(2015-04-01), 1-13 1610-2940 21:4<1 2015 21 894 https://doi.org/10.1007/s00894-015-2631-3 text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s00894-015-2631-3 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Yadava Umesh Department of Physics, D.D.U. Gorakhpur University, 273009, Gorakhpur, India aut NATIONALLICENCE 700 1- Shukla Bindesh Department of Physics, D.D.U. Gorakhpur University, 273009, Gorakhpur, India aut NATIONALLICENCE 700 1- Roychoudhury Mihir Department of Physics, D.D.U. Gorakhpur University, 273009, Gorakhpur, India aut NATIONALLICENCE 700 1- Kumar Devesh Department of Applied Physics, Babasaheb Bhimrao Ambedkar University, Vidya Vihar, Rae Bareilly Road, 226025, Lucknow, India aut NATIONALLICENCE 773 0- Journal of Molecular Modeling Springer Berlin Heidelberg 21/4(2015-04-01), 1-13 1610-2940 21:4<1 2015 21 894