Targeting p75NTR, NGF, and NOTCH Signaling: Network Pharmacology Insights into Neurodegenerative and Mental Health Therapies from Salinispora and Streptomyces Actinobacteria

Marine Actinobacteria, notably Salinispora and Streptomyces species, are emerging as promising sources of bioactive compounds with therapeutic potential for neurodegenerative and mental health disorders. This study employs a network pharmacology approach to investigate how compounds from these marine microbes interact with key genes in the p75 Neurotrophin receptor (p75NTR), nerve growth factor (NGF), and NOTCH signaling pathways, all of which are crucial in neurodegenerative processes. A comprehensive screening pipeline, involving absorption, distribution, metabolism, and excretion (ADME) evaluation (drug-likeness, oral bioavailability, blood-brain barrier permeability) and in silico toxicity profiling across five major toxicity categories, was conducted to identify bioactive compounds with favorable pharmacokinetic properties and non-toxic profiles. Top candidates were selected based on their significant interactions with genes related to the aforementioned signaling pathways. Notably, Salinosporamide A (NPI-0052 and its fused-lactam-lactone form) from Salinispora, and Bonactin, Azamerone, and Methoxyneihumicin from Streptomyces, were identified as key compounds. These showed interactions with genes such as MAPK1, NCSTN, APH1A, AR, JAK2, and PSENEN, which are crucial in regulating p75NTR-mediated, NGF, and NOTCH signaling. The p75NTR pathway is involved in neuronal survival, apoptosis, and synaptic function; its disruption contributes to neurodegeneration. NGF signaling supports neuronal differentiation and survival, with its dysregulation linked to Alzheimer's and similar diseases. The NOTCH pathway governs neurodevelopment, cell communication, and synaptic plasticity, with perturbations associated with schizophrenia and neurodegenerative disorders.