Abstract
In this study, we investigated the delivery of synthetic neurosteroids into MCF-7 human breast adenocarcinoma cells via Organic Anionic Transporting Polypeptides (OATPs) (pH 7.4 and 5.5) to identify the structural components required for OATP-mediated cellular uptake and to get insight into brain drug delivery. Then, we identified structure-uptake relationships using in-house developed OATP1A2 homology model to predict binding sites and modes for the ligands. These binding modes were studied by molecular dynamics simulations to rationalize the experimental results. Our results show that carboxylic acid needs to be at least at 3 carbon-carbon bonds distance from amide bond at the C-3 position of the androstane skeleton and have an amino group to avoid efflux transport. Replacement of hydroxyl group at C-3 with any of the 3, 4, and 5-carbon chained terminal carboxylic groups improved the affinity. We attribute this to polar interactions between carboxylic acid and side-chains of Lys33 and Arg556. The additional amine group showed interactions with Glu172 and Glu200. Based on transporter capacities and efficacies, it could be speculated that the functionalization of acetyl group at the C-17 position of the steroidal skeleton might be explored further to enable OAT1A2-mediated delivery of neurosteroids into the cells and also across the blood-brain barrier.
Highlights
Alzheimer’s disease (AD) is the most complex neurodegenerative disorder, leading to gradual loss of cognition and eventually death
Cellular uptake of synthetic neurosteroids 1–11 (syntheses have been reported in our Cellular uptake of synthetic neurosteroids 1–11 was evaluated by using the MCF-7 was evaluated by using the MCF-7 cell line, which is known to express several Organic Anionic Transporting Polypeptides (OATPs) cinoma; Michigan Cancer Foundation-7) cell line, which is known to express several and efflux transporters [34,35]
More detailed transport mechanisms were invesby performing Eadie-Hofstee plot analysis, which revealed that almost all synthesized tigated by performing Eadie-Hofstee plot analysis, which revealed that almost all syntheneurosteroids 1–11 had two distinct transport mechanisms
Summary
Alzheimer’s disease (AD) is the most complex neurodegenerative disorder, leading to gradual loss of cognition and eventually death. In AD-brain, beta-amyloid (Aβ) deposits accumulate into neurons, making neurons lose their capacity to respond to stimuli and become proinflammatory contributing to neuronal death. Central nervous system (CNS) diseases often meet the limited penetration of drugs by the blood-brain-barrier (BBB) [9]. Over 98% of drugs do not cross BBB at acceptable concentrations for therapeutic treatment. The BBB protects the brain tissue from xenobiotics and microbes, while allowing movement of oxygen and essential substances via specific transporters [10]. Carrier-mediated active uptake is the primary transport mechanism for most of the CNS-drugs [11], and endogenous solute carriers (SLCs) have a major role in their CNS disposition [12,13]
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