The ribosomal protein S6 kinase beta-1 (RPS6KB1), also known as p70S6 kinase, plays a crucial role in various disease-related conditions such as diabetes, obesity, and cancer. Its activity is ...regulated by phosphorylation events, including phosphorylation of Threonine 389 in the hydrophobic motif by the mammalian target of rapamycin complex 1 (mTORC1) and phosphorylation of Threonine 229 in the activation loop by PDK1 (phosphoinositide-dependent kinase 1). However, other phenomena connected to RPS6KB1 remain unknown. In this study, we employed virtual screening and molecular docking techniques on the molecules in the ZINC library to identify potential inhibitors. Molecular dynamics (MD) simulations and MMGBSA calculations were carried out on promising compounds to determine their binding affinity and stability. We also evaluated the drug-likeness properties of the selected compounds. A comparative study between the native RPS6KB1 structure, co-crystal ligands, and the shortlisted molecules from the ZINC dataset was carried out. The identified molecules possess significant potential for future
and
studies, paving the way for developing effective cancer treatments.Communicated by Ramaswamy H. Sarma.
SARS-CoV-2 requires serine protease, transmembrane serine protease 2 (TMPRSS2), and cysteine proteases, cathepsins B, L (CTSB/L) for entry into host cells. These host proteases activate the spike ...protein and enable SARS-CoV-2 entry. We herein performed genomic-guided gene set enrichment analysis (GSEA) to identify upstream regulatory elements altering the expression of TMPRSS2 and CTSB/L. Further, medicinal compounds were identified based on their effects on gene expression signatures of the modulators of TMPRSS2 and CTSB/L genes. Using this strategy, estradiol and retinoic acid have been identified as putative SARS-CoV-2 alleviation agents. Next, we analyzed drug-gene and gene-gene interaction networks using 809 human targets of SARS-CoV-2 proteins. The network results indicate that estradiol interacts with 370 (45%) and retinoic acid interacts with 251 (31%) human proteins. Interestingly, a combination of estradiol and retinoic acid interacts with 461 (56%) of human proteins, indicating the therapeutic benefits of drug combination therapy. Finally, molecular docking analysis suggests that both the drugs bind to TMPRSS2 and CTSL with the nanomolar to low micromolar affinity. The results suggest that these drugs can simultaneously target both the entry pathways of SARS-CoV-2 and thus can be considered as a potential treatment option for COVID-19.
Fullerene C60, a unique sphere-shaped molecule consisting of carbon, has been proved to have inhibitory effects on many diseases. However, the applications of C60 in medicine have been severely ...hindered by its complete insolubility in water and low solubility in almost all organic solvents. In this study, the water-soluble C60 derivatives and the C60 binding protein's structures were collected from the literature. The selected proteins fall into several groups, including acetylcholinesterase, glutamate racemase, inosine monophosphate dehydrogenase, lumazine synthase, human estrogen receptor alpha, dihydrofolate reductase and N-myristoyltransferase. The C60 derivatives were docked into the binding sites in the proteins. The binding affinities of the C60 derivatives were calculated. The bindings between proteins and their known inhibitors or native ligands were also characterized in the same way. The results show that C60 derivatives form good interactions with the binding sites of different protein targets. In many cases, the binding affinities of C60 derivatives are better than those of known inhibitors and native ligands. This study demonstrates the interaction patterns of C60 derivatives and their binding partners, which will have good impact on the fullerene-based drug discovery.
Background: The present study was carried out to test the antioxidant activity of lactoferrin as a dietary supplement to alleviate the effects of oxidative stress induced by mercury toxicity. ...Hematological and biochemical assays were employed to evaluate the ameliorating effects of lactoferrin. Methods: Sixty male Wistar rats were allotted randomly and equally into three groups; animals in Group 1 served as untreated control, animals in Group 2 were administered orally with mercuric chloride (HgCl 2 ) at the dose of 6 mg/kg bw/day, and animals in Group 3 were administered with HgCl 2 at the same dose and orally dosed with lactoferrin (400 mg/kg bw/day). Hematological indices (erythrocytic and total leukocytic counts, hemoglobin concentration%, and packed cell volume, (PCV%), and biochemical parameters (serum and homogenates of liver and kidney tissues) were assessed in all animals. Serum and tissue homogenate levels of total thiols, glutathione (GSH), catalase, and total antioxidant capacity (TAC) represented the antioxidant markers. The oxidation markers were represented by H 2 O 2 and malondialdehyde (MDA). Results: Compared to the untreated control group, animals in Group 2 (administered with HgCl 2 ) exhibited significantly increased levels of serum enzymes (alanine transferase (ALT), aspertate transferase (AST), and alkaline phosphatase), urea, blood urea nitrogen, creatinine, H 2 O 2 , and MDA. These animals showed significantly decreased levels of erythrocytic and total leukocytic counts, hemoglobin concentration, PCV%, total proteins, total thiols, GSH, catalase, and TAC. The hematological and biochemical changes were comparatively reversed toward the control levels in animals of Group 3 (administered with HgCl 2 and orally dosed with lactoferrin). The reversed levels of hematological and biochemical parameters were significantly different compared to Group 2. Conclusions: Based on the encountered amelioration of the assayed hematological and biochemical parameters in animals treated with HgCl 2 and given lactoferrin, it could be concluded that lactoferrin as a dietary supplement might function as an efficient antioxidant to alleviate the oxidative stress induced by mercury toxicity.
Pantothenate synthetase protein plays a pivotal role in the biosynthesis of coenzyme A (CoA), which is a crucial molecule involved in a number of cellular processes including the metabolism of fatty ...acid, energy production, and the synthesis of various biomolecules, which is necessary for the survival of Mycobacterium tuberculosis ( Mtb ). Therefore, inhibiting this protein could disrupt CoA synthesis, leading to the impairment of vital metabolic processes within the bacterium, ultimately inhibiting its growth and survival. This study employed molecular docking, structure-based virtual screening, and molecular dynamics (MD) simulation to identify promising phytochemical compounds targeting pantothenate synthetase for tuberculosis (TB) treatment. Among 239 compounds, the top three (rutin, sesamin, and catechin gallate) were selected, with binding energy values ranging from −11 to −10.3 kcal/mol, and the selected complexes showed RMSD (<3 Å) for 100 ns MD simulation time. Furthermore, molecular mechanics generalized Born surface area (MM/GBSA) binding free energy calculations affirmed the stability of these three selected phytochemicals with binding energy ranges from −82.24 ± 9.35 to −66.83 ± 4.5 kcal/mol. Hence, these identified natural plant-derived compounds as potential inhibitors of pantothenate synthetase could be used to inhibit TB infection in humans.
The inflicted chaos instigated by the SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) globally continues with the emergence of novel variants. The current global outbreak is aggravated ...by the manifestation of novel variants, which affect the effectiveness of the vaccine, attachment with hACE2 (human Angiotensin-converting enzyme 2) and immune evasion. Recently, a new variant named University Hospital Institute (IHU) (B.1.640.2) was reported in France in November 2021 and is spreading globally affecting public healthcare. The B.1.640.2 SARS-CoV-2 strain revealed 14 mutations and 9 deletions in spike protein. Thus, it is important to understand how these variations in the spike protein impact the communication with the host. A protein coupling approach along with molecular simulation protocols was used to interpret the variation in the binding of the wild type (WT) and B.1.640.2 variant with hACE2 and Glucose-regulating protein 78 (GRP78) receptors. The initial docking scores revealed a stronger binding of the B.1.640.2-RBD with both the hACE2 and GRP78. To further understand the crucial dynamic changes, we looked at the structural and dynamic characteristics and also explored the variations in the bonding networks between the WT and B.1.640.2-RBD (receptor-binding domain) in association with hACE2 and GRP78, respectively. Our findings revealed that the variant complex demonstrated distinct dynamic properties in contrast to the wild type due to the acquired mutations. Finally, to provide conclusive evidence on the higher binding by the B.1.640.2 variant the TBE was computed for each complex. For the WT with hACE2 the TBE was quantified to be-61.38 ± 0.96 kcal/mol and for B.1.640.2 variant the TBE was estimated to be −70.47 ± 1.00 kcal/mol. For the WT-RBD-GRP78 the TBE -was computed to be 32.32 ± 0.56 kcal/mol and for the B.1.640.2-RBD a TBE of −50.39 ± 0.88 kcal/mol was reported. This show that these mutations are the basis for higher binding and infectivity produced by B.1.640.2 variant and can be targeted for drug designing against it.
Communicated by Ramaswamy H. Sarma
Abstract Background: Melatonin is a peptide neurohormone naturally synthesized in the brain by the pineal gland. The basic function of melatonin is related to the causation and regulation of the ...sleep–wake cycle (circadian cycle). Cadmium (Cd) is a hazardous heavy metal and its toxic effects induce extensive tissue damage. The present study was undertaken to elucidate the efficiency of exogenous melatonin in attenuating Cd-induced oxidative stress. Methods: The experimental rats were allotted into four groups ( n = 20), designated as untreated control, melatonin accessed, Cd exposed, and Cd exposed with access. Results: The hematological and biochemical parameters (serum and tissues) of Cd-exposed rats were significantly altered. Cd-exposed rats that received melatonin demonstrated increased erythrocytic indices; showed significantly increased levels of total proteins, catalase, total thiols, and glutathione; and exhibited decreased levels of blood Cd, urea, creatinine, bilirubin, malondialdehyde, and hydrogen peroxide. Conclusions: It was concluded that melatonin has an efficient antioxidant activity in attenuating oxidative stress induced by Cd.
The liquid whey is a byproduct produced during cheese making. Cadmium is a highly hazardous heavy metal with cumulative toxic effects. The present research work was done to clarify the possible role ...of whey proteins in alleviating cadmium-induced oxidative stress. The used rats were allotted equally and randomly into three experimental groups; untreated control, cadmium-exposed, and cadmium-exposed and whey protein-administered groups. The biochemical and haematological assays of rats exposed to cadmium (group 2) manifested significant alterations compared to those of untreated control animals. Concerning the biochemical serum profile, group 3 animals showed relatively increased levels of total proteins, significant increments of total thiols, glutathione, total antioxidant capacity (TAC), and catalase, and significant decrements in the levels of blood cadmium, alanine transferase (ALT), aspartate transferase (AST), alkaline phosphatase (ALP), creatinine, urea, bilirubin, hydrogen peroxide (H2O2), and malondialdehyde (MDA) compared to the animals exposed to cadmium (group 2). Homogenates of liver and kidney tissues obtained from group 3 animals demonstrated similar results to that revealed by the serum assay. It was concluded that whey proteins as a dietary supplement can offer potential antioxidant properties that enable these supplementary proteins to alleviate cadmium-induced oxidative stress.
FrbJ is a member of the Fe2+/α‐ketoglutarate‐dependent dioxygenase family which hydroxylates the natural product FR‐900098 of Streptomyces rubellomurinus, yielding the phosphonate antibiotic ...FR‐33289. Here, the crystal structure of FrbJ, which shows structural homology to taurine dioxygenase (TauD), a key member of the same family, is reported. Unlike other members of the family, FrbJ has an unusual lid structure which consists of two β‐strands with a long loop between them. To investigate the role of this lid motif, a molecular‐dynamics simulation was performed with the FrbJ structure. The molecular‐dynamics simulation analysis implies that the lid‐loop region is highly flexible, which is consistent with the fact that FrbJ has a relatively broad spectrum of substrates with different lengths. Interestingly, an access tunnel is found at the back of the active site which connects the putative binding site of α‐ketoglutarate to the solvent outside.
The crystal structure of the dioxygenase FrbJ is reported. An access tunnel was found at the back of the active site, which connects the putative binding site for α‐ketoglutarate to the solvent.
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