Identification of hydantoin based Decaprenylphosphoryl-β-d-Ribose Oxidase (DprE1) inhibitors as antimycobacterial agents using computational tools

Abstract

Tuberculosis (TB) is one of the emerging infectious diseases in the world. DprE1 (Decaprenylphosphoryl-β-d-ribose 2′-epimerase), an enzyme accountable for mycobacterial cell wall synthesis was the first drug gable target based on discoveries of inhibitors via HTS (high throughput screening). Since then, many literature reports have been published so far enlightening varieties of chemical scaffolds acting as inhibitors of DprE1. Herein, in our present study, we have developed statistically robust GA-MLR (genetic algorithm multiple linear regression), atom-based as well as field based-3D-QSAR models. Both atom-based as well as field based-3D-QSAR models (internally as well as externally validated) were obtained with robust Training set, R2 > 0.69 and Test set, Q2 > 0.50. We have also developed top ranked 5 point hypothesis AAAHR_1 among 14 CPHs (common pharmacophore hypotheses). We found that our dataset molecule had more docking score (XP mode = − 9.068 kcal/mol) than the standards isoniazid and ethambutol; when docked into binding pockets of enzyme 4P8C with Glide module. We further queried our best docked dataset molecule 151 for ligand based virtual screening using “SwissSimilarity” platform. Among 9 identified hits, we found ZINC12196803 had best binding energies and docking score (docking score = − 9.437 kcal/mol, MMGBSA dgBind = − 70.508 kcal/mol). Finally, our molecular dynamics studies for 1.2–100 ns depicts that these complexes are stable. We have also carried out in-silico ADMET predictions, Cardiac toxicity, ‘SwissTargetPredictions’ and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) binding energy calculations for further explorations of dataset as well as hit molecules. Our current studies showed that the hit molecule ZINC12196803 may enlighten the path for future developments of DprE1 inhibitors.

A Chitosan Hydrochloride Mediated, Simple and Efficient Approach for the Synthesis of Hydrazones, their in vitro Antimycobacterial Evaluations, and Molecular Modeling Studies (Part III)

“…he RMSF was used to investigate the fluctuation of the complexes in the function of time. 55 The protein RMSF value was also retained below 4.5 Å. The N-terminal has high fluctuation compared with C terminal.…”

“…The backbone changes for (N, Cα, C) of protein were analyzed via RMSD and RMSF evaluations. 55 Protein-ligand RMSD graph shows that the complex has fluctuations over the simulation period of 5 ns and got stabilized after 7.5 ns of simulation time.…”

“…In our current analysis, we performed MD simulation analysis in order to establish stability of docked molecule, 3b towards 3IVX target chosen. 55 The total duration of simulation was kept at 20ns, which comprises of 288 residues of chain A, 4299 atoms, and charge of -4. Ensemble class was kept at NTP mode (Figure 5).…”

“…To establish probable binding modes [43][44][45][46][47][48][49][50][51][52][53][54][55][56][57] of synthesized compounds 3a-j as antimycobacterial agents, we carried out molecular docking simulations on the target enzyme, Mycobacterium tuberculosis pantothenate synthetase (PS) (pdb id: 3IVX, Resolution: 1.73 Å), which includes an internal inbound ligand, FG6 ({2-[(1-benzofuran-2-ylsulfonyl)carbamoyl]-5-methoxy-1H-indol-1-yl}acetic acid). It is important to note that this target has a key role in the pathogenicity or virulence of M. tuberculosis.…”

A Review on the Some Biological Activities of the Hydantoin Derivatives

“…It also suggests that this limits repeated high-frequency firings. It also increases Ca binding to phospholipids present in neuronal membranes 12,13 .…”