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

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.

Identification of New Potent Human Uncoupling Protein 1 (UCP1) Agonists Using Virtual Screening and in vitro Approaches

“…In order to refine the modeled UCP1 protein, molecular dynamics (MD) simulation was performed on Desmond v3.8 modules from the Schrödinger suite software . The protein structure was prepared using the Protein Preparation Wizard module in the Schrödinger software . The NPT temperature is fixed to 300 K, the pressure is set to 1.01 bar, and the operation is 50 ns.…”

Design, sythesis and evaluation of a series of 3- or 4-alkoxy substituted phenoxy derivatives as PPARs agonists

“…Shaw Research, New York, NY, 2015), running CentOS7.1 Linux operating system. The operation was mainly conducted on well-prepared structures in several phases [38]. Initially, a model system for generating a solvated system was built with the solvent model set to predefined SPC [33], box shape to orthorhombic and box size calculation to Buffer method through the System Builder panel [39, 40].…”

Insights into multifaceted activities of CysK for therapeutic interventions

“…These structural determinants extracted from crystal structures of various peptide-enzyme complexes formed the basis for developing peptide/nonpeptide inhibitors. Since then several studies have reported inhibitors against open conformation of CysK from different organisms with affinities for CysK generally ranging from millimolar to micromolar concentrations (Jean Kumar et al 2013;Spyrakis et al 2013;Yadava et al 2015;Kant et al 2018). Natural compounds as potential inhibitors of CysK have also been reported, however, the leads from these studies require rational modifications to achieve better efficacy (Nagpal et al 2012;Mori et al 2015Mori et al , 2018.…”