Abstract
The recent success of small-molecule kinase inhibitors as anticancer drugs has generated significant interest in their application to other clinical areas, such as disorders of the central nervous system (CNS). However, most kinase inhibitor drug candidates investigated to date have been ineffective at treating CNS disorders, mainly due to poor blood–brain barrier (BBB) permeability. It is, therefore, imperative to evaluate new chemical entities for both kinase inhibition and BBB permeability. Over the last 35 years, marine biodiscovery has yielded 471 natural products reported as kinase inhibitors, yet very few have been evaluated for BBB permeability. In this study, we revisited these marine natural products and predicted their ability to cross the BBB by applying freely available open-source chemoinformatics and machine learning algorithms to a training set of 332 previously reported CNS-penetrant small molecules. We evaluated several regression and classification models, and found that our optimised classifiers (random forest, gradient boosting, and logistic regression) outperformed other models, with overall cross-validated model accuracies of 80%–82% and 78%–80% on external testing. All 3 binary classifiers predicted 13 marine-derived kinase inhibitors with appropriate physicochemical characteristics for BBB permeability.
Highlights
The discovery of bryostatin 1, a macrolide isolated from the bryozoan Bugula neritina [1], marks one of early inputs of marine bioprospecting to kinase drug discovery
As we explored the blood–brain barrier (BBB) permeability for structurally diverse compounds (KDs, marine-derived kinase inhibitors (MDKIs)), we were mindful that we might exceed the property space of CNS-penetrant small molecules (CPSMs) used in our models
We constructed and used quantitative structure–property relationship (QSPR) models to predict the ability of marine-derived kinase inhibitors (MDKIs) to pass through the blood–brain barrier (BBB), based on their physicochemical properties
Summary
The discovery of bryostatin 1, a macrolide isolated from the bryozoan Bugula neritina [1], marks one of early inputs of marine bioprospecting to kinase drug discovery. The Yuspa and Pettit groups reported bryostatin 1 as the first marine-derived protein kinase C (PKC) modulator inhibiting the allosteric binding site for endogenous messengers (e.g., diacylglycerol) and oncogenic phorbol esters (e.g., 12-O-tetredecanoylphorbol-13-acetate) known to induce skin carcinogenesis [2]. In addition to being extensively tested, clinically, for various tumours [3,4], bryostatin 1 appears promising in enhancing memory in animal models, and is in Phase IIa for the treatment of Alzheimer’s disease at the Blanchette Rockefeller Neurosciences Institute [5]. 1, several drug discovery campaigns have been established over the years to reveal marine natural products potentially active against targeted kinases.
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