Burkholderia cepacia has emerged as a significant infectious agent that exhibits resistance to major classes of antibiotics and novel therapeutic approaches are necessitated to address this pathogen. ...Glutamate racemase (GR) has been revealed as highly potent and safe drug target by pan-genome analysis. It plays role in the interconversion of L-Glutamate to D-Glutamate and remains an essential element of the peptidoglycan layer. Docking guided virtual screening is carried out predicting a lead molecule: “(R)-1-((5-((1R, 6R)-6-carboxycyclohexa-2, 4-dien-1-yl) thiazol-2-yl) methyl)-3-oxopiperazin-1-ium” possess the best fitting conformation to the target. It is found that heterocyclic ring of the molecule has a key role in the binding affinity of the target protein. During simulation, the inhibitor interacts with the allosteric site, allowing the heterocyclic ring to be positioned at the adjacent substrate binding site. Local secondary structures interconversion is seen regularly in both chains of the protein. The radial distribution function investigated Leu24 as closely placed at 1.9 Å with an average g (r) value 0.8 to the binding site residues during the course of simulation. The density of the interactive space shows that Leu24 and Asn85 are the most active residues with average binding energies of −2.65 kcal/mol and −2.36 kcal/mol, respectively and affirms strong hydrogen bonding. Total binding energies in both MMPB/GBSA results in −21.13 kcal/mol and −36.41 kcal/mol are contributing heavily towards the stability. Interestingly, the Waterswap approach exhibits accurate binding energies of −20.16 kcal/mol. This chemical entity is adjacent to medicinally active molecules and in line with the previous research which showed thiazol subunits and its derivatives bearing many biological functions. In order to validate compound antibacterial activity, it is necessary to investigate the biological potency of the compound using biological assays and could be promising for experimentalists in the future to address this multi-drug resistant pathogen.
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•Pan-genome investigation enlightened highly attractive drug targets.•Glutamate racemase identified as a best drug candidate.•A high affinity binder as lead molecule was identified.•Leu24 is the major residue that binds to atom O17 of lead throughout simulation.
Antibiotics resistance by bacterial pathogens is a major concern to public health worldwide resulting in high health care costs and rising mortality. Subtractive proteomics prioritized ...D-alanyl-D-alanine carboxypeptidas (DacB) enzyme from Enterobacter cloacae ATCC 13047 as a potential candidate for drugs designing to block pathogen cell wall biosynthesis. Virtual screening of an antibacterial library against the target unraveled a hit compound (2-(1-methylsulfonylpiperidin-3-yl)methyl-6-(1H-pyrazol-4-yl) pyrazine) showing high affinity and stability with the target. The N-methyl-N-propyl-methanesulfonamide of the compound is seen as a closed affinity towards domain involving strong hydrogen bonds with Ser41, Lys44, Ser285, and Asn287. The 4-methyl-1H-pyrazole is posed towards the open cavity of domain I and II and formed hydrophobic and hydrophilic contacts. The system is highly stable with average carbon-alpha deviations of 1.69 Å over trajectories of 400-ns. Three vital residues projected: Arg437, Arg438 and Leu400 from enzyme pocket
Radial distribution function (RDF) assay, which actively engaged the inhibitor. Further confirmation is done by estimating binding free energies, which confirms the very low delta energy of -7.24 kcal/mol in Generalized Born (GB) method and -7.4363 kcal/mol in Poisson-Boltzmann (PB) method. WaterSwap calculations were performed that revealed the energies highly converged, an agreement on good system stability. Lastly, three DacB mutants were created to investigate the role of functional active residues and a decline in binding affinity of the residues was noticed. These computational results provide a gateway for experimentalists to further confirm their efficacy both in-vitro and in-vivo.Communicated by Ramaswamy H. Sarma.
GLS1 enzymes (Glutaminase C (GAC) and kidney-type Glutaminase (KGA)) are gaining prominence as a target for tumor treatment including lung, breast, kidney, prostate, and colorectal. To date, several ...medicinal chemistry studies are being conducted to develop new and effective inhibitors against GLS1 enzymes. Telaglenastat, a drug that targets the allosteric site of GLS1, has undergone clinical trials for the first time for the therapy of solid tumors and hematological malignancies. A comprehensive computational investigation is performed to get insights into the inhibition mechanism of the Telaglenastat. Some novel inhibitors are also proposed against GLS1 enzymes using the drug repurposing approach using 2D-fingerprinting virtual screening method against 2.4 million compounds, application of pharmacokinetics, Molecular Docking, and Molecular Dynamic (MD) Simulations. A TIP3P water box of 10 Å was defined to solvate both enzymes to improve MD simulation reliability. The dynamics results were validated further by the MMGB/PBSA binding free energy method, RDF, and AFD analysis. Results of these computational analysis revealed a stable binding affinity of Telaglenastat, as well as an FDA approved drug Astemizole (IC50 ∼ 0.9 nM) and a novel para position oriented methoxy group containing Chembridge compound (Chem-64284604) that provides an effective inhibitory action against GAC and KGA.
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•MD simulation results revealed that the efficiency of inhibitors is associated to greater shift of the catalytic loop.•Astemizole (IC50 ∼0.9 nM) was discovered that might be repurposed against KGA and GAC to overcome their expression.•An allosteric Chembridge compound Chem-64284604 with methoxy group gives better results than Telaglenastat.
The discovery of novel drug targets of a genome that can bind with high affinity to drug-like compounds is a significant challenge in drug development. Streptococcus gordonii initiates dental plaque ...formation and endocarditis by entering into the blood stream, usually after oral trauma. The prolonged use of antibiotics is raising a problem of multi-drug resistance and lack of an optimal therapeutic regime that necessitates the drug discovery of vital importance in curing various infections. To overcome this dilemma, the in silico approach paves the way for identification and qualitative characterization of promising drug targets for S. gordonii that encompass three phases of analyses. The present study deciphers drug target genomes of S. gordonii in which 93 proteins were identified as potential drug targets and 16 proteins were found to be involved in unique metabolic pathways. Highlighted information will convincingly render to facilitate selection of S. gordonii proteins for successful entry into drug design pipelines.
•In silico approach to identify and characterize potential therapeutic candidates in S. gordonii.•Identification and characterization of proteins of S. gordonii which is required for growth•A total of 16 protein targets out of 93 drug targets are involved in the pathogen specific 7 pathways.
In this study, we delve into the electronic structure, spectroscopic, and optical properties of five benzo derivatives of pyridine, namely, 5-(4-chlorophenyl)-2-fluoropyridine (1), ...2-fluoro-5-(4-fluorophenyl)pyridine (2), 4-(2-fluoropyridin-5-yl)phenol (3), 5-(2,3-dichlorophenyl)-2-fluoropyridine (4), and 5-(5-bromo-2-methoxyphenyl)-2-fluoropyridine (5). Utilizing quantum chemical density functional theory calculations at the B3LYP and Perdew–Burke–Ernzerhof levels of theory combined with the 6-311G(d,p) and 6-311++G(d,p) basis sets, we investigated the electronic and optical characteristics of these compounds. Band structure calculations were conducted for their crystalline structures, revealing a direct band gap varying from 3.018 to 3.558 eV, with the valence band maximum and conduction band minimum located at the G point in the Brillouin zone. The optical properties were analyzed, including the dielectric functions, reflectivity, and refractive index. Notably, reflectivity was found to be minimal in the photon energy range of 0.0–3.0 eV, and the static refractive index, n(0), ranged from 1.55 to 1.70. The research also involved assessing the reactivity of the compounds through calculation of the frontier orbital energy gaps (ΔE), indicating a significant charge transfer and high reactivity. Additionally, we performed frequency analysis to unveil the Fourier-transform infrared spectra of compounds 1–5 at room temperature. Molecular electrostatic potential surfaces of the optimized structures were employed to map the electrophilic and nucleophilic regions of the compounds. This investigation provides a comprehensive understanding of the electronic and optical properties of these pyridine derivatives, shedding light on their potential applications in optoelectronics.
Orientia tsutsugamushi, the causative agent of scrub typhus has been found resistant to various classes of antibiotics such as penicillins, gentamycin and cephalosporins. Review of current literature ...suggests that the prevalence of scrub typhus has increased globally. Therefore, the current study has aimed at exploring the genome of O. tsutsugamushi to identify potential drug target proteins that can be used for developing novel antibiotics against the pathogen. Subtractive proteomics approach has revealed FIS as a potential drug target protein involved in two component system (TCS), a signaling pathway crucial for bacteria to survive and adjust in changing environmental conditions. Molecular docking studies have revealed compound-356 (CHEMBRIDGE-10040641-3710.356) as a potential inhibitor in both chains A and B of the FIS protein. Simulation results suggest that the docked complex has remained stable and compact throughout the 200 ns run. Significant conformational changes including the hinge motion was observed in the DNA binding domain. Furthermore, the presence of salt bridge between GLU910 and ARG417, rearrangement of interaction residues and displacement of ATP in the central AAA + domain upon binding to the inhibitor were also observed playing a role in stabilizing the protein structure.
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•FIS protein revealed as potential drug target involved in TCSs pathway.•Compound-356 acts as potential inhibitor in both chains A and B of the FIS protein.•ATP plays significant role in holding the ligand within the central AAA + domain.•Hinge motion in the DBD is observed during simulation.•Inhibitor in the active pocket keeps protein stable without disrupting its hinge motion.
Roxadustat, a small-molecule inhibitor of hypoxia-inducible factor prolyl hydroxylase domain 2 (HIF-PHD2) has been recently overruled by the American Food and Drug Administration (FDA) in Phase 3 ...clinical trials. This study provides insights into the dynamics of Roxadustat with PHD2 and proposes two FDA-approved drugs; Pemetrexed and Valrubicin to treat chronic kidney disease (CKD). Role of chemical scaffolds such as synthetic pyrimidine-based antifolate is found critical for PHD2 inhibitory activity, which is concurrent with the experimental findings for stimulating Endogenous erythropoietin (EPO) gene expression. Furthermore, Fe+2 and Mn+2 in solution are essential for imparting structural stability to the screened carboxylic and non-carboxylic acid drugs. Comparative analysis of FDA-approved drugs namely, Roxadustat, two-hit carboxylic, and non-carboxylic-acid type compounds (Pemetrexed and Valrubicin), as well as the control ligands (KU1 and 4JR), unveil structural dynamics of Roxadustat and its failure. However, the proposed FDA compounds, Pemetrexed and Valrubicin, used to treat mesothelioma, non-small cell lung cancer, and bladder cancer should be subjected to in vitro analysis for renal anemia.
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•Roxadustat toxic trait is both experimental and computational.•Pemetrexed, an FDA-approved drug is screened as a potential PHD2 inhibitor.•Fe+2 and Mn+2 are directly involved in stabilization of metal center active site.•ASP 218 is essential for metal ions to maintain their coordination geometries.
SARS-Cov-2 Omicron variant and its highly transmissible sublineages amidst news of emerging hybrid variants strengthen the evidence of its ability to rapidly spread and evolve giving rise to ...unprecedented future waves. Owing to the presence of isolated RBD, monomeric and trimeric Cryo-EM structures of spike protein in complex with ACE2 receptor, comparative analysis of Alpha, Beta, Gamma, Delta, and Omicron assist in a rational assessment of their probability to evolve as new or hybrid variants in future. This study proposes the role of hydration forces in mediating Omicron function and dynamics based on a stronger interplay between protein and solvent with each Covid wave. Mutations of multiple hydrophobic residues into hydrophilic residues underwent concerted interactions with water leading to variations in charge distribution in Delta and Omicron during molecular dynamics simulations. Moreover, comparative analysis of interacting moieties characterized a large number of mutations lying at RBD into constrained, homologous and low-affinity groups referred to as mutational drivers inferring that the probability of future mutations relies on their function. Furthermore, the computational findings reveal a significant difference in angular distances among variants of concern due 3 amino acid insertion (EPE) in Omicron variant that not only facilitates tight domain organization but also seems requisite for characterization of mutational processes. The outcome of this work signifies the possible relation between hydration forces, their impact on conformation and binding affinities, and viral fitness that will significantly aid in understanding dynamics of drug targets for Covid-19 countermeasures. The emerging scenario is that hydration forces and hydrophobic interactions are crucial variables to probe in mutational analysis to explore conformational landscape of macromolecules and reveal the molecular origins of protein behaviors.
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