Computer-Aided Drug Design Applied to Marine Drug Discovery: Meridianins as Alzheimer’s Disease Therapeutic Agents

Abstract

Computer-aided drug discovery/design (CADD) techniques allow the identification of natural products that are capable of modulating protein functions in pathogenesis-related pathways, constituting one of the most promising lines followed in drug discovery. In this paper, we computationally evaluated and reported the inhibitory activity found in meridianins A–G, a group of marine indole alkaloids isolated from the marine tunicate Aplidium, against various protein kinases involved in Alzheimer’s disease (AD), a neurodegenerative pathology characterized by the presence of neurofibrillary tangles (NFT). Balance splitting between tau kinase and phosphate activities caused tau hyperphosphorylation and, thereby, its aggregation and NTF formation. Inhibition of specific kinases involved in its phosphorylation pathway could be one of the key strategies to reverse tau hyperphosphorylation and would represent an approach to develop drugs to palliate AD symptoms. Meridianins bind to the adenosine triphosphate (ATP) binding site of certain protein kinases, acting as ATP competitive inhibitors. These compounds show very promising scaffolds to design new drugs against AD, which could act over tau protein kinases Glycogen synthetase kinase-3 Beta (GSK3β) and Casein kinase 1 delta (CK1δ, CK1D or KC1D), and dual specificity kinases as dual specificity tyrosine phosphorylation regulated kinase 1 (DYRK1A) and cdc2-like kinases (CLK1). This work is aimed to highlight the role of CADD techniques in marine drug discovery and to provide precise information regarding the binding mode and strength of meridianins against several protein kinases that could help in the future development of anti-AD drugs.

Meridianins and Lignarenone B as Potential GSK3β Inhibitors and Inductors of Structural Neuronal Plasticity

“…Our experiments aimed to predict the absorption, distribution, metabolism, excretion and toxicity (ADMET) properties of potential therapeutic compounds, and thus, ADMET properties prediction for meridianins A-G and lignarenone B are reported ( Table 2). Meridianins display some solubility problems (logS> 5 indicate not too much solubility), especially meridianin F, as well as difficulties to penetrate the BBB [29], a problem that is also shared by lignarenone B. This is also in agreement with the obtained logP values.…”

“…These HBs are established with residues F67, V70, K85, D133, V135, R141, Q185, C199 and D200. Most of the listed aminoacidic residues are configuring the ATP binding pocket ( Figure 4B) [16,29,30,72]. For the substrate binding pocket, we found sixteen important HBs.…”

“…The modelled protein structures and the marine molecules were employed as input of the calculations executed over each of the two cavities using Itzamna software tool [51]. More details on this approach can be found in the literature [29,30].…”

“…ADMETer, a software tool containing supper vector regression (SVR) and supper vector machine (SVM) ADMET machine-learning (ML) predictive models, was used to assess the ADMET properties (LogS, LogP, Caco2, blood-brain-barrier (BBB), plasma-protein binding (PPB), P-glycoprotein (Pgp), human ether-a-go-go gene hERG) of meridianin A-G and lignarenone B [29,66]. LogS reflects the solubility of the molecule in water (>5 indicate bad solubility).…”

“…Marine natural products, comprising a huge variety of chemical structures and being a serendipitous source of new molecules, could play a key role on this need [26][27][28][29][30][31]. In fact, the biomedical and pharmacological potential of marine natural products is known to be still underexplored [32,33].…”