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AbstractPoly (ADP-ribose) polymerase-1 (PARP1) inhibition strategy for cancer treatment is gaining advantage particularly in patients having a mutation in BRCA1/BRCA2 gene. To date, four drugs have obtained FDA approval and some inhibitors are in clinical trials. To identify more potent PARP1 inhibitors extensive research is going on to enrich the library of PARP1 inhibitors with compounds belonging to different classes. We employed an integrated virtual screening approach to identify potential PARP1 inhibitors. The sequential support vector machine (SVM) and pharmacophore model based virtual screening was carried out on the Maybridge library. The obtained hits were docked in the binding site of the PARP1 catalytic domain and nine drug-like compounds showing good ADME properties and form critical molecular interactions with the binding site residues were considered for the in vitroPARP1 inhibition assay. MD simulations were performed to decipher the stability of the PARP1-ligand complexes. Hydrogen bond interactions were also probed for their stability during MD simulations. We have identified three compounds (BTB02767, GK01172, and KM09200) showing 50% inhibition of PARP1 enzyme activity at 25 μM. BTB02767 and KM09200 have phthalazinone scaffold, while GK01172 bears a thiophene carboxamide scaffold, which could be a new chemotype of PARP1 inhibitors. In conclusion, GK01172 may serve as an important compound for further development of PARP1 inhibitors containing thiophene carboxamide scaffold.Communicated by Ramaswamy H. Sarma

AbstractTrypanothione reductase of Leishmania donovaniis a flavin adenine dinucleotide containing homodimeric protein essential for parasite survival. The flavoenzyme utilizes nicotinamide adenine dinucleotide phosphate in the reaction to convert oxidized trypanothione to reduced trypanothione which is further used up by tryparedoxin/tryparedoxin peroxidase system to neutralize the reactive oxygen species generated by the macrophages. Some of the drugs previously reported against the disease include sodium stibogluconate, miltefosine and amphotericin B. However, due to the resistance and toxicity problem associated with these molecules, there is an urgent need to develop new drugs against L. donovani. Trypanothione reductase of L. donovaniis one such essential target whose inhibition could lead to a decline in parasite growth. In this work, we have performed a computational studies using Maybridge library of chemical compounds to identify potential inhibitors of Trypanothione reductase of L. donovani. Structure-based virtual screening method in combination with molecular docking was employed to identify and prioritize 30 compounds which were further subjected to molecular dynamics simulation. Ten compounds which showed stable ligand root-mean-square deviation plot, c-alpha backbone and root-mean-square fluctuation were considered for trypanothione reductase inhibition assay and subsequent inhibition studies of parasite growth. Enzyme inhibition assay resulted in shortlisting of four compounds that were found to inhibit Trypanothione reductase of L. donovani. Subsequently, the anti-leishmanial screening highlighted one compound as the potential anti-leishmanial agent, with IC50value of 15.2 µM, that can be further optimised with medicinal chemistry efforts to improve its activity.Communicated by Ramaswamy H. Sarma