Serum and glucocorticoid-regulated kinase 1 (SGK1) is a serine/threonine kinase that works under acute transcriptional control by several stimuli, including serum and glucocorticoids. It plays a significant role in the cancer progression and metastasis, as it regulates inflammation, apoptosis, hormone release, neuro-excitability, and cell proliferation. SGK1 has recently been considered as a potential drug target for cancer, diabetes, and neurodegenerative diseases. In the present study, we have performed structure-based virtual high-throughput screening of natural compounds from the ZINC database to find potential inhibitors of SGK1. Initially, hits were selected based on their physicochemical, absorption, distribution, metabolism, excretion, and toxicity (ADMET), and other drug-like properties. Afterwards, PAINS filter, binding affinities estimation, and interaction analysis were performed to find safe and effective hits. We found four compounds bearing appreciable binding affinity and specificity towards the binding pocket of SGK1. The docking results were complemented by all-atom molecular dynamics simulation for 100 ns, followed by MM/PBSA, and principal component analysis to investigate the conformational changes, stability, and interaction mechanism of SGK1 in-complex with the selected compound ZINC00319000. Molecular dynamics simulation results suggested that the binding of ZINC00319000 stabilizes the SGK1 structure, and it leads to fewer conformational changes. In conclusion, the identified compound ZINC00319000 might be further exploited as a scaffold to develop promising inhibitors of SGK1 for the therapeutic management of associated diseases, including cancer.

Cyclin-Dependent Kinase 6 (CDK6) plays an important role in cancer progression, and thus, it is considered as an attractive drug target in anticancer therapeutics. This study presents an evaluation of dietary phytochemicals, capsaicin, tocopherol, rosmarinic acid, ursolic acid, ellagic acid (EA), limonene, caffeic acid, and ferulic acid for their potential to inhibit the activity of CDK6. Molecular docking and fluorescence binding studies revealed appreciable binding affinities of these compounds to the CDK6. Among them, EA shows the highest binding affinity for CDK6, and thus a molecular dynamics simulation study of 200 ns was performed to get deeper insights into the binding mechanism and stability of the CDK6-EA complex. Fluorescence binding studies revealed that EA binds to the CDK6 with a binding constant of K = 10⁷ M⁻¹ and subsequently inhibits its enzyme activity with an IC₅₀ value of 3.053 µM. Analysis of thermodynamic parameters of CDK6-EA complex formation suggested a hydrophobic interaction driven process. The treatment of EA decreases the colonization of cancer cells and induces apoptosis. Moreover, the expression of CDK6 has been downregulated in EA-treated human breast cancer cell lines. In conclusion, this study establishes EA as a potent CDK6 inhibitor that can be further evaluated in CDK6 directed anticancer therapies.

Microtubule affinity-regulating kinase (MARK4) plays a key role in Alzheimer’s disease (AD) development as its overexpression is directly linked to increased tau phosphorylation. MARK4 is a potential drug target of AD and is thus its structural features are employed in the development of new therapeutic molecules. Donepezil (DP) and rivastigmine tartrate (RT) are acetylcholinesterase (AChE) inhibitors and are used to treat symptomatic patients of mild to moderate AD. In keeping with the therapeutic implications of DP and RT in AD, we performed binding studies of these drugs with the MARK4. Both DP and RT bound to MARK4 with a binding constant (K) of 10⁷ M⁻¹. The temperature dependency of binding parameters revealed MARK−DP complex to be guided by static mode while MARK−RT complex to be guided by both static and dynamic quenching. Both drugs inhibited MARK4 with IC₅₀ values of 5.3 μM (DP) and 6.74 μM (RT). The evaluation of associated enthalpy change (ΔH) and entropy change (ΔS) implied the complex formation to be driven by hydrogen bonding making it seemingly strong and specific. Isothermal titration calorimetry further advocated a spontaneous binding. In vitro observations were further complemented by the calculation of binding free energy by molecular docking and interactions with the functionally-important residues of the active site pocket of MARK4. This study signifies the implications of AChE inhibitors, RT, and DP in Alzheimer’s therapy targeting MARK4.

The bacteria expressing New Delhi Metallo-β-lactamase-1 (NDM-1) can hydrolyze all β-lactam antibiotics including carbapenems, causing multi-drug resistance. The worldwide emergence and dissemination of gene bla_NDM-1 (produces NDM-1) in hospital and community settings, rising problems for public health. Indeed, there is an urgent need for NDM-1 inhibitors to manage antibiotic resistance. Here, we have identified novel non-β-lactam ring-containing inhibitors of NDM-1 by applying a high-throughput virtual screening of lead-like subset of ZINC database. The screened compounds were followed for the molecular docking, the molecular dynamics simulation, and then enzyme kinetics assessment. The adopted screening procedure funnels out five novel inhibitors of NDM-1 including ZINC10936382, ZINC30479078, ZINC41493045, ZINC7424911, and ZINC84525623. The molecular mechanics-generalized born surface area and molecular dynamics (MD) simulation showed that ZINC84525623 formed the most stable complex with NDM-1. Furthermore, analyses of the binding pose after MD simulation revealed that ZINC84525623 formed two hydrogen bonds (electrostatic and hydrophobic interaction) with key amino acid residues of the NDM-1 active site. The docking binding free energy and docking binding constant for the ZINC84525623 and NDM-1 interaction were estimated to be −11.234 kcal/mol, and 1.74 × 10⁸ M⁻¹ respectively. Steady-state enzyme kinetics in the presence of ZINC84525623 show the decreased catalytic efficiency (i.e., k_cat/K_m) of NDM-1 on various antibiotics. The findings of this study would be helpful in identifying novel inhibitors against other β-lactamases from a pool of large databases. Furthermore, the identified inhibitor (ZINC84525623) could be developed as efficient drug candidates.

Background: The emergence and dissemination of SARS-CoV-2 has caused high mortality and enormous economic loss. Rapid development of new drug molecules is the need of hour to fight COVID-19. However, the conventional approaches of drug development are time consuming and expensive. Here, we have adopted a computational approach to identify lead molecules from nature. Ligands from natural compounds library available at Selleck Inc (L1400) have been screened for their ability to bind and inhibit the main protease (3CLpro) of SARS-CoV-2. Methods: The natural compounds library of Selleck Inc. (Catalog No. L1400) were retrieved from www.selleckchem.com. It contains 2230 compounds in sdf format, curated from natural sources. Prior to molecular docking, all the ligands were prepared by adding hydrogen atoms and merging them with non-polar hydrogen atoms. Gasteiger partial charges were added, rotatable bonds were defined, and the energies were minimized using MMFF94 forcefield (11,12). The three-dimensional coordinates of the main protease (Mpro), also known as 3C-like protein (3CLpro), was downloaded from the protein databank available at https://www.rcsb.org/structure/6LU7. The structure was solved to a resolution of 2.16 Å and is bound with a peptide-like inhibitor (N3)(8). The structure of target was prepared for molecular docking by adding hydrogen atoms, Kollman united atom type charges and solvation parameters using AutoDock Tool (ADT) (13). Results: We found that Kaempferol, Quercetin, and Rutin were bound at the substrate binding pocket of 3CLpro with high affinity (105-106 M-1) and interact with the active site residues such as His41 and Cys145 through hydrogen bonding and hydrophobic interactions. In fact, the binding affinity of Rutin (~106 M-1) was much higher than Chloroquine (~103 M-1) and Hydroxychloroquine (~104 M-1), and the reference drug Remdesivir (~105 M-1). Conclusion: The results suggest that natural compounds such as flavonoids have the potential to be developed as novel inhibitors of SARS-CoV-2 with a comparable/higher potency as that of Remdesivir. However, their clinical usage on COVID-19 patients is a subject of further investigations and clinical trials.

Sphingolipid metabolites have emerged as critical players in the regulation of various physiological processes. Ceramide and sphingosine induce cell growth arrest and apoptosis, whereas sphingosine-1-phosphate (S1P) promotes cell proliferation and survival. Here, we present an overview of sphingolipid metabolism and the compartmentalization of various sphingolipid metabolites. In addition, the sphingolipid rheostat, a fine metabolic balance between ceramide and S1P, is discussed. Sphingosine kinase (SphK) catalyzes the synthesis of S1P from sphingosine and modulates several cellular processes and is found to be essentially involved in various pathophysiological conditions. The regulation and biological functions of SphK isoforms are discussed. The functions of S1P, along with its receptors, are further highlighted. The up-regulation of SphK is observed in various cancer types and is also linked to radio- and chemoresistance and poor prognosis in cancer patients. Implications of the SphK/S1P signaling axis in human pathologies and its inhibition are discussed in detail. Overall, this review highlights current findings on the SphK/S1P signaling axis from multiple angles, including their functional role, mechanism of activation, involvement in various human malignancies, and inhibitor molecules that may be used in cancer therapy.