BMDMS-NP: A comprehensive ESI-MS/MS spectral library of natural compounds.

The Bioinformatics & Molecular Design Research Center Mass Spectral Library - Natural Products (BMDMS-NP) is a library containing the mass spectra of natural compounds, especially plant specialized metabolites. At present, the library contains the electrospray ionization tandem mass spectrometry (ESI-MS/MS) spectra of 2739 plant metabolites that are commercially available. The contents of the library were made comprehensive by incorporating data generated under various experimental conditions for compounds with diverse molecular structures. The structural diversity of the BMDMS-NP data was evaluated using molecular fingerprints, and it was sufficiently exhaustive enough to represent the structures of the natural products commercially available. The MS/MS spectra of each metabolite were obtained with different types/brands of ion traps (tandem-in-time) or combinations of mass analyzers (tandem-in-space) at multiple collision energies. All spectra were measured repeatedly in each environment because variations can occur in spectra, even under the same conditions. Moreover, the probability, separability of searching, and transferability of this spectral library were evaluated against those of MS/MS libraries, namely: NIST17 and MoNA.

Investigation of Hot Spot Region in XIAP Inhibitor Binding Site by Fragment Molecular Orbital Method.

X-linked inhibitor of apoptosis protein (XIAP) is an important regulator of cancer cell survival whose BIR3 domain (XIAP-BIR3) recognizes the Smac N-terminal tetrapeptide sequence (AVPI), making it an attractive protein-protein interaction (PPI) target for cancer therapies. We used the fragment molecular orbital (FMO) method to study the binding modes and affinities between XIAP-BIR3 and a series of its inhibitors (1-8) that mimic the AVPI binding motif; the inhibitors had common interactions with key residues in a hot spot region of XIAP-BIR3 (P1-P4 subpockets) with increased binding affinity mainly attributed to specific interactions with the P1 and P4 subpockets. Based on the structural information from FMO results, we proposed a novel XIAP natural product inhibitor, neoeriocitrin 10, which was derived from our preciously reported XIAP-BIR3 inhibitor 9, can be used as a highly potent candidate for XIAP-BIR3 inhibition. We also performed pair interaction energy decomposition analysis to investigate the binding energies between specific binding residues and individual ligands, showing that the novel natural product neoeriocitrin 10 had a higher binding affinity than epicatechin gallate 9. Molecular docking and dynamics simulations were performed to explore the mode of binding between 10 and XIAP-BIR3, demonstrating that 10 binds more strongly to the P1 and P4 pockets than 9. Overall, we present a novel natural product, neoeriocitrin 10, and demonstrate that the FMO method can be used to identify hot spots in PPIs and design new compounds for XIAP inhibition.