Sahoo, A. K. | Search bioRxiv

bioRxiv2020

MeFSAT: A curated natural product database specific to secondary metabolites of medicinal fungi

Fungi are a rich source of secondary metabolites which constitutes a valuable and diverse chemical space of natural products. Medicinal fungi have been used in traditional medicine to treat human ailments for centuries. To date, there is no devoted resource on secondary metabolites and therapeutic uses of medicinal fungi. Such a dedicated resource compiling dispersed information on medicinal fungi across published literature will facilitate ongoing efforts towards natural product based drug discovery. Here, we present the first comprehensive manually curated database on Medicinal Fungi Secondary metabolites And Therapeutics (MeFSAT) that compiles information on 184 medicinal fungi, 1830 secondary metabolites and 149 therapeutics uses. Importantly, MeFSAT contains a non-redundant in silico natural product library of 1830 secondary metabolites along with information on their chemical structures, computed physicochemical properties, drug-likeness properties, predicted ADMET properties, molecular descriptors and predicted human target proteins. By comparing the physicochemical properties of secondary metabolites in MeFSAT with other small molecules collections, we find that fungal secondary metabolites have high stereochemical complexity and shape complexity similar to other natural product libraries. Based on multiple scoring schemes, we have filtered a subset of 228 drug-like secondary metabolites in MeFSAT database. By constructing and analyzing chemical similarity networks, we show that the chemical space of secondary metabolites in MeFSAT is highly diverse. The compiled information in MeFSAT database is openly accessible at: https://cb.imsc.res.in/mefsat/.

bioinformatics↗

bioRxiv2020

Concerted interactions between multiple gp41 trimers and the target cell lipidome may be required for HIV-1 entry

The HIV-1 envelope glycoprotein gp41 mediates the fusion between viral and host cell membranes leading to virus entry and target cell infection. Despite years of research, important aspects of this process such as the number of gp41 trimers involved and how they orchestrate the rearrangement of the lipids in the apposed membranes along the fusion pathway remain obscure. To elucidate these molecular underpinnings, we performed coarse-grained molecular dynamics simulations of HIV-1 virions pinned to the CD4 T cell membrane by different numbers of gp41 trimers. We built realistic cell and viral membranes by mimicking their respective lipid compositions. We found that a single gp41 was inadequate for mediating fusion. Lipid mixing between membranes, indicating the onset of fusion, was efficient when 3 or more gp41 trimers pinned the membranes. The gp41 trimers interacted strongly with many different lipids in the host cell membrane, triggering lipid configurational rearrangements, exchange, and mixing. Simpler membranes, comprising fewer lipid types, displayed strong resistance to fusion, revealing the crucial role of the lipidomes in HIV-1 entry. Performing simulations at different temperatures, we estimated the free energy barrier to lipid mixing, and hence membrane stalk formation, with 4 tethering gp41 trimers to be ~6.2 kcal/mol, a >4-fold reduction over estimates without gp41. Together, these findings present molecular-level, quantitative insights into the early stages of gp41-mediated HIV-1 entry. Preventing the requisite gp41 molecules from tethering the membranes or altering membrane lipid compositions may be potential intervention strategies. SIGNIFICANCEInteractions between viral envelope proteins and host cell surface receptors leading to HIV-1 entry are well studied, however the role of membrane lipids remains obscure, although entry hinges on lipid mixing and the fusion of viral and cell membranes. We performed detailed simulations of HIV-1 and target cell membranes tethered by viral gp41 trimeric proteins to elucidate the proteo-lipidic contributions to viral entry. We found that the cooperative effects of multiple gp41 trimers and natural lipidomes of the membranes facilitate membrane fusion. The functional domains of gp41 altered local lipid concentrations, reduced membrane repulsions, and facilitated inter-membrane lipid mixing. These molecular-level insights offer a glimpse of the cryptic mechanisms underlying HIV-1 entry and suggest new interventions to combat HIV-1 infection.

biophysics↗