Binding Free Energy (BFE) Calculations and Quantitative Structure–Activity Relationship (QSAR) Analysis of Schistosoma mansoni Histone Deacetylase 8 (smHDAC8) Inhibitors

Abstract

Histone-modifying proteins have been identified as promising targets to treat several diseases including cancer and parasitic ailments. In silico methods have been incorporated within a variety of drug discovery programs to facilitate the identification and development of novel lead compounds. In this study, we explore the binding modes of a series of benzhydroxamates derivatives developed as histone deacetylase inhibitors of Schistosoma mansoni histone deacetylase (smHDAC) using molecular docking and binding free energy (BFE) calculations. The developed docking protocol was able to correctly reproduce the experimentally established binding modes of resolved smHDAC8–inhibitor complexes. However, as has been reported in former studies, the obtained docking scores weakly correlate with the experimentally determined activity of the studied inhibitors. Thus, the obtained docking poses were refined and rescored using the Amber software. From the computed protein–inhibitor BFE, different quantitative structure–activity relationship (QSAR) models could be developed and validated using several cross-validation techniques. Some of the generated QSAR models with good correlation could explain up to ~73% variance in activity within the studied training set molecules. The best performing models were subsequently tested on an external test set of newly designed and synthesized analogs. In vitro testing showed a good correlation between the predicted and experimentally observed IC50 values. Thus, the generated models can be considered as interesting tools for the identification of novel smHDAC8 inhibitors.

Design, synthesis, and biological and computational evaluation of novel oxindole derivatives as inhibitors of Aurora A Kinase and SARS-CoV-2 Spike/Host ACE2 Interaction

“…Meanwhile, 4BYI was chosen for Aurora A kinase. This structure was found to have a co-crystalized ligand, imidazo [4,5-b]pyridine in its structure [47].…”

5-chloro-3-(2-(2,4-dinitrophenyl) hydrazono)indolin-2-one: synthesis, characterization, and biochemical and computational screening against SARS-CoV-2

“…Table 1 shows the various mutations carried out on the Wuhan strain or the wild type (WT) spike RBD/ACE2 to derive the various mutants (β, δ, λ and ο). G339D, S371L, S373P, S375F, K417N, N440K, G446S, S477N, T478K, E484A, Q493R, G496S, Q498R, N501Y, Y505H Docking towards the SARS-CoV-2 Spike RBD/ACE2 and the Human PD_1/PD_L1 Docking procedures were performed using the Glide program in a similar way as previously demonstrated (Simoben et al 2018(Simoben et al , 2021Divsalar et al 2020). In this work three grid boxes for the SARS-CoV-2 viral protein RBD/ACE2 human receptor (PDB ID: 6M0J) and one grid box for the human protein complex PD_1/PD_L1 (PDB ID: 4ZQK, Zak et al 2015) were generated and using speci c protein residues.…”

Histone Deacetylase (HDAC) Inhibitors for the Treatment of Schistosomiasis

“…Inhibitor 8 was also cocrystallized with smHDAC8 confirming the conserved binding mode of benzhydroxamic acid derived inhibitors (Figure 2B). In parallel, the developed inhibitors were analyzed by docking and molecular dynamics simulation in order to rationalize the determined in vitro data [62].…”