EVOLAND 2 FRAGMENT OF TIME TRIAL

developed the Bioinformatics and Molecular Design Research Center Mass Spectral Library-Natural Products (BMDMS-NP), which was sufficiently exhaustive to represent the structural diversity of commercially available natural products. Although natural products possess vast chemical diversity and are a rich source of novel compound classes for biological studies, challenges related to the quality control of materials and commercial availability exist. Natural products have been considered an important source of lead and candidate compounds for new medicines in drug discovery because they provide efficient and wide coverage of drug-like chemical spaces. Therefore, suppressing MMP-9 via the hemopexin domain would be a good strategy for inhibiting MMP-9-mediated pathological processes. The expression levels of MMP-9 in patients with breast cancer are correlated with poor prognosis. MMP-9 is involved in tumor growth initiation and invasion in basal and squamous cell carcinomas and is associated with the radial growth phase of melanoma and tumor angiogenesis.

MMP-9 is a 92 kDa type-IV collagenase that can degrade type-IV collagen and other extracellular matrices. Moreover, among MMPs with the hemopexin domain, the gelatinase subfamily (MMP-2 and MMP-9) is important in collagen degradation through the digestion of gelatin, which is generated by collagenases. Since the hemopexin domains are less conserved among MMPs, they have been considered a suitable site for the development of selective inhibitors of MMPs. To overcome the adverse effects caused by MMP inhibitors targeting the zinc-binding site, the inhibition of the less conserved and non-catalytic domains of MMPs has been suggested to increase the specificity and selectivity.

EVOLAND 2 FRAGMENT OF TIME TRIAL

Although many MMP inhibitors have been developed, they exhibit adverse effects in the clinical trial stage because of the lack of specificity between the target MMP and other members of the MMP family, as the zinc-binding site is common in all MMPs. The catalytic domain of MMPs contains a zinc-ion-binding motif. These 23 MMPs have multiple domains and typically include a signal sequence, propeptide, catalytic domain, linker domain, and hemopexin domain. Twenty-three MMPs have been identified in humans, including secreted and membrane-bound forms, sharing common structural and functional domains. MMPs are involved in multiple cellular processes, including proliferation, migration, cancer invasion, host defense, angiogenesis, and metastasis. Matrix metalloproteinases (MMPs) are calcium-dependent zinc-containing endopeptidases that degrade extracellular matrix proteins and participate in tissue remodeling and signaling events. Overall, we present laetanine 9 and genkwanin 10 for MMP-9 and demonstrate that the novel FMO-based workflow with a quantum mechanical approach is promising to discover potent natural product inhibitors of MMP-9, satisfying the pharmacophore model and good binding affinity. Laetanine 9 and genkwanin 10 bind to MMP-9 with a dissociation constant (K D) of 21.6 and 0.614 μM, respectively.

By applying this workflow to MMP-9, we proposed two potent natural product inhibitors (laetanine 9 and genkwanin 10) that interact with hotspot residues of the hemopexin domain of MMP-9. In the two targets, the FMO method outperformed the Glide docking score and MM/PBSA methods.

In binding affinity prediction, we made a scoring function with the FMO method and applied the function to two protein targets (acetylcholinesterase and fibroblast growth factor 1 receptor) from DUD-E benchmark sets. The workflow integrates qualitative pharmacophore modeling, quantitative binding affinity prediction, and a raw material search of natural product inhibitors with the BMDMS-NP library. Here, we identified two potent natural product inhibitors of the non-catalytic hemopexin domain of MMP-9 using a novel quantum mechanical fragment molecular orbital (FMO)-based virtual screening workflow. Among the MMP isoforms, MMP-9 regulates cancer invasion, rheumatoid arthritis, and osteoarthritis by degrading extracellular matrix proteins present in the tumor microenvironment and cartilage and promoting angiogenesis. Matrix metalloproteinases (MMPs) are calcium-dependent zinc-containing endopeptidases involved in multiple cellular processes.

Evoland 2 fragment of time