Structure-based identification of potential inhibitors of ribosomal protein S6 kinase 1, targeting cancer therapy: a combined docking and molecular dynamics simulations approach.

Ribosomal protein S6 kinase 1 (S6K1), commonly known as P70-S6 kinase 1 (p70S6), is a key protein kinase involved in cellular signaling pathways that regulate cell growth, proliferation, and metabolism. Its significant role is reported in the PIK3/mTOR signaling pathway and is associated with various complex diseases, including diabetes, obesity, and different types of cancer. Due to its involvement in various physiological and pathological conditions, S6K1 is considered as an attractive target for drug design and discovery. One way to target S6K1 is by developing small molecule inhibitors that specifically bind to its ATP-binding site, preventing its activation and thus inhibiting downstream signaling pathways necessary for cell growth and survival. In this study, we have conducted a multitier virtual screening of a pool of natural compounds to identify potential S6K1 inhibitors. We performed molecular docking on IMPPAT 2.0 library and selected top hits based on their binding affinity, ligand efficiency, and specificity towards S6K1. The selected hits were further assessed based on different filters of drug-likeliness where two compounds (Hecogenin and Glabrene) were identified as potential leads for S6K1 inhibition. Both compounds showed appreciable affinity, ligand efficiency and specificity towards S6K1 binding pocket, drug-like properties, and stable protein-ligand complexes in molecular dynamics (MD) simulations. Finally, our study has suggested that Hecogenin and Glabrene can be potential S6K1 inhibitors which are presumably implicated in the therapeutic management of associated diseases such as diabetes, obesity, and varying types of cancer.Communicated by Ramaswamy H. Sarma.

Investigating MARK4 inhibitory potential of Bacopaside II: Targeting Alzheimer's disease.

Microtubule affinity regulating kinase 4 (MARK4) is known to hyperphosphorylate tau protein, which subsequently causes Alzheimer's disease (AD). MARK4 is a well-validated drug target for AD; thus, we employed its structural features to discover potential inhibitors. On the other hand, complementary and alternative medicines (CAMs) have been used for the treatment of numerous diseases with little side effects. In this regard, Bacopa monnieri extracts have been extensively used to treat neurological disorders because of their neuroprotective roles. The plant extract is used as a memory enhancer and a brain tonic. Bacopaside II is a major component of Bacopa monnieri; thus, we studied its inhibitory effects and binding affinity towards the MARK4. Bacopaside II show a considerable binding affinity for MARK4 (K = 107 M-1) and inhibited kinase activity with an IC50 value of 5.4 µM. To get atomistic insights into the binding mechanism, we performed Molecular dynamics (MD) simulation studies for 100 ns. Bacopaside II binds strongly to the active site pocket residues of MARK4 and a number of hydrogen bonds remain stable throughout the MD trajectory. Our findings provide the basis for the therapeutic implication of Bacopaside and its derivatives in MARK4-related neurodegenerative diseases, especially AD and neuroinflammation.

Human disease-associated calmodulin mutations alter calcineurin function through multiple mechanisms.

Calmodulin (CaM) is a ubiquitous, calcium-sensing protein that regulates a multitude of processes throughout the body. In response to changes in [Ca2+], CaM modifies, activates, and deactivates enzymes and ion channels, as well as many other cellular processes. The importance of CaM is highlighted by the conservation of an identical amino acid sequence in all mammals. Alterations to CaM amino acid sequence were once thought to be incompatible with life. During the last decade modifications to the CaM protein sequence have been observed in patients suffering from life-threatening heart disease (calmodulinopathy). Thus far, inadequate or untimely interaction between mutant CaM and several proteins (LTCC, RyR2, and CaMKII) have been identified as mechanisms underlying calmodulinopathy. Given the extensive number of CaM interactions in the body, there are likely many consequences for altering CaM protein sequence. Here, we demonstrate that disease-associated CaM mutations alter the sensitivity and activity of the Ca2+-CaM-enhanced serine/threonine phosphatase calcineurin (CaN). Biophysical characterization by circular dichroism, solution NMR spectroscopy, stopped-flow kinetic measurements, and MD simulations provide mechanistic insight into mutation dysfunction as well as highlight important aspects of CaM Ca2+ signal transduction. We find that individual CaM point mutations (N53I, F89L, D129G, and F141L) impair CaN function, however, the mechanisms are not the same. Specifically, individual point mutations can influence or modify the following properties: CaM binding, Ca2+ binding, and/or Ca2+kinetics. Moreover, structural aspects of the CaNCaM complex can be altered in manners that indicate changes to allosteric transmission of CaM binding to the enzyme active site. Given that loss of CaN function can be fatal, as well as evidence that CaN modifies ion channels already associated with calmodulinopathy, our results raise the possibility that altered CaN function contributes to calmodulinopathy.

Bioactive Phytoconstituents as Potent Inhibitors of Tyrosine-Protein Kinase Yes (YES1): Implications in Anticancer Therapeutics.

Tyrosine-protein kinase Yes (YES1) belongs to the Tyrosine-protein kinase family and is involved in several biological activities, including cell survival, cell-cell adhesion, cell differentiation, and cytoskeleton remodeling. It is highly expressed in esophageal, lung, and bladder cancers, and thus considered as an attractive drug target for cancer therapy. In this study, we performed a virtual screening of phytoconstituents from the IMPPAT database to identify potential inhibitors of YES1. Initially, the molecules were retrieved on their physicochemical properties following the Lipinski rule of five. Then binding affinities calculation, PAINS filter, ADMET, and PASS analyses followed by an interaction analysis to select safe and clinically better hits. Finally, two compounds, Glabrene and Lupinisoflavone C (LIC), with appreciable affinities and a specific interaction towards the AlphaFold predicted structure of YES1, were identified. Their time-evolution analyses were carried out using an all-atom molecular dynamics (MD) simulation, principal component analysis, and free energy landscapes. Altogether, we propose that Glabrene and LIC can be further explored in clinical settings to develop anticancer therapeutics targeting YES1 kinase.