Computational analysis and molecular dynamics simulation of high-risk single nucleotide polymorphisms of the ADAM10 gene.

Polymorphisms of the disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) are linked to pathophysiological changes in lung inflammation, cancer, Alzheimer's disease (AD), encephalopathy, liver fibrosis, and cardiovascular diseases. In this study, we predicted the pathogenicity of ADAM10 non-synonymous single nucleotide polymorphisms (nsSNPs) in a wide array of mutation analyzing bioinformatics tools. We retrieved 423 nsSNPs from dbSNP-NCBI for the analysis, and 13 were predicted deleterious by each of the ten tools: SIFT, PROVEAN, CONDEL, PANTHER-PSEP, SNAP2, SuSPect, PolyPhen-2, Meta-SNP, Mutation Assessor and Predict-SNP. Further assessment of amino acid sequences, homology models, conservation profiles, and inter-atomic interactions identified C222G, G361E and C639Y as the most pathogenic mutations. We validated this prediction through structural stability analysis using DUET, I-Mutant Suite, SNPeffect and Dynamut. Molecular dynamics simulations and principal component analysis also indicated considerable instability of the C222G, G361E and C639Y variants. Therefore, these ADAM10 nsSNPs could be candidates for diagnostic genetic screening and therapeutic molecular targeting.Communicated by Ramaswamy H. Sarma.

A computational study to target necroptosis via RIPK1 inhibition.

The human receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is a critical necroptosis regulator implicated in cancer, psoriasis, ulcerative colitis, rheumatoid arthritis, Alzheimer's disease, and multiple sclerosis. Currently, there are no specific RIPK1 antagonists in clinical practice. In this study, we took a target-based computational approach to identify blood-brain-barrier-permeable potent RIPK1 ligands with novel chemotypes. Using molecular docking, we virtually screened the Marine Natural Products (MNP) library of 14,492 small molecules. Initial 18 hits were subjected to detailed ADMET profiling for bioavailability, brain penetration, druglikeness, and toxicities and eventually yielded 548773-66-6 as the best ligand. RIPK1 548773-66-6 binding was validated through duplicated molecular dynamics (MD) simulations where the co-crystallized ligand L8D served as a reference. Trajectory analysis indicated negligible Root-Mean-Square-Deviations (RMSDs) of the best ligand 548773-66-6 relative to the protein backbone: 0.156 ± 0.043 nm and 0.296 ± 0.044 nm (mean ± standard deviations) in two individual simulations. Visual inspection confirmed that 548773-66-6 occupied the RIPK1 ligand-binding pocket associated with the kinase activation loop. Further computations demonstrated consistent hydrogen bond interactions of the ligand with the residue ASP156. Binding free energy estimation also supported stable interactions of 548773-66-6 and RIPK1. Together, our in silico analysis predicted 548773-66-6 as a novel ligand for RIPK1. Therefore, 548773-66-6 could be a viable lead for inhibiting necroptosis in central nervous system inflammatory disorders.Communicated by Ramaswamy H. Sarma.

Cofilin Signaling in the CNS Physiology and Neurodegeneration.

All eukaryotic cells are composed of the cytoskeleton, which plays crucial roles in coordinating diverse cellular functions such as cell division, morphology, migration, macromolecular stabilization, and protein trafficking. The cytoskeleton consists of microtubules, intermediate filaments, and actin filaments. Cofilin, an actin-depolymerizing protein, is indispensable for regulating actin dynamics in the central nervous system (CNS) development and function. Cofilin activities are spatiotemporally orchestrated by numerous extra- and intra-cellular factors. Phosphorylation at Ser-3 by kinases attenuate cofilin's actin-binding activity. In contrast, dephosphorylation at Ser-3 enhances cofilin-induced actin depolymerization. Cofilin functions are also modulated by various binding partners or reactive oxygen species. Although the mechanism of cofilin-mediated actin dynamics has been known for decades, recent research works are unveiling the profound impacts of cofilin dysregulation in neurodegenerative pathophysiology. For instance, oxidative stress-induced increase in cofilin dephosphorylation is linked to the accumulation of tau tangles and amyloid-beta plaques in Alzheimer's disease. In Parkinson's disease, cofilin activation by silencing its upstream kinases increases α-synuclein-fibril entry into the cell. This review describes the molecular mechanism of cofilin-mediated actin dynamics and provides an overview of cofilin's importance in CNS physiology and pathophysiology.