Multitargeting the Action of 5-HT6 Serotonin Receptor Ligands by Additional Modulation of Kinases in the Search for a New Therapy for Alzheimer's Disease: Can It Work from a Molecular Point of View?

Abstract

In view of the unsatisfactory treatment of cognitive disorders, in particular Alzheimer's disease (AD), the aim of this review was to perform a computer-aided analysis of the state of the art that will help in the search for innovative polypharmacology-based therapeutic approaches to fight against AD. Apart from 20-year unrenewed cholinesterase- or NMDA-based AD therapy, the hope of effectively treating Alzheimer's disease has been placed on serotonin 5-HT₆ receptor (5-HT₆R), due to its proven, both for agonists and antagonists, beneficial procognitive effects in animal models; however, research into this treatment has so far not been successfully translated to human patients. Recent lines of evidence strongly emphasize the role of kinases, in particular microtubule affinity-regulating kinase 4 (MARK4), Rho-associated coiled-coil-containing protein kinase I/II (ROCKI/II) and cyclin-dependent kinase 5 (CDK5) in the etiology of AD, pointing to the therapeutic potential of their inhibitors not only against the symptoms, but also the causes of this disease. Thus, finding a drug that acts simultaneously on both 5-HT₆R and one of those kinases will provide a potential breakthrough in AD treatment. The pharmacophore- and docking-based comprehensive literature analysis performed herein serves to answer the question of whether the design of these kind of dual agents is possible, and the conclusions turned out to be highly promising.

Keywords: 5-HT6 ligands; Alzheimer’s disease; CDK5; MARK4; ROCKI; ROCKII; dementia.

Figure 1

The structural variety of 5-HT₆R antagonists: (a) compounds 1 [23,24], 2 [25], 3 [26,27,28,29], 4 [30,31,32] and 5 [33] investigated in clinical trials; (b) compounds in the early stages of R&D: the non-indole and non-sulfone derivatives 6 [34], 7 [35], 8 [36,37], 9 [38,39], 10 [40,41]and 11 [42] and non-basic antagonists 12 [43] and 13 [43,44]. The affinity for 5-HT₆R expressed with K_i (nM). Procognitive effects in the Novel Object Recognition (NOR) test for 8–10. at the dose shown [36,37,38,39,40,41].

Figure 2

Pharmacophore model of the 5-HT₆R ligands: aromatic moiety (R7), hydrogen bond acceptor (A1), hydrophobic moiety (H2).

Figure 3

5-HT₆R ligand (CHEMBL267615, K_i = 16 nM) mapped to the pharmacophore model of the 5-HT₆R ligands.

Figure 4

5-HT₆R ligand (CHEMBL267615) docked to the 5-HT₆R homology model.

Figure 5

Distribution of docking score values to 5-HT₆R homology model.

Figure 6

Representatives of weak and moderate MARK4 inhibitors with the activity descriptors; (a) the weak 3-N-aryl substituted-2-heteroarylchromoneinhibitor 14 [54] in comparison to the moderate 3-benzoylcoumarinMARK4 inhibitor; (b) the moderate inhibitors from various heterocyclic families 15 [55], 16 [56], 17 [57], 18 [58], 19 [59], 20 [60], 21 [61]; (c) MARK4 inhibitory properties of rivastigmine and donepezil [50]. To compare the activity expressed in various ways (IC50, K_d or %inhibition at a given concentration), the formal inhibition activity descriptor (FA) was used, i.e.,: FA = pIC₅₀ (IC₅₀); FA = pK_d (K_d), FA = p(test concentration/0.02 × %inhibition).

Figure 7

The most potent MARK4 inhibitors (IC₅₀ < 100 nM) 22 [62], 23, 24, 26 [63], 25 [64], 27 [65], 28 [66].

Figure 8

General structures (A,B) of the potent MARK4 inhibitors (IC₅₀ < 1 µM) described [14,15,16,17,18,19]. The common feature of pyrimidine 2,4,5-trisubstituted (A) or 2-substituted-4,5-cyclic (B) in blue, the favorable substituents in rectangular frames.

Figure 9

Examples of the most active MARK4 inhibitors: (A) mapped on the 5-HT₆R pharmacophore model; (B) docked to the homology model of 5-HT₆R; (a) 23, (b) 24, (c) 25.

Figure 10

Examples of potent ROCK inhibitors from different chemical classes: 29 [94], 31 [95], 32 [95], 33 [96], 34 [97], 35 [98], 36 [99], 37 [100], 40 [102], 41 [103], 42 [106], 43 [108], 44 [CHEMBL1988581]. ROCK inhibiting potency expressed with either IC₅₀ or K_i values (nM).

Figure 11

Common structural elements found in 5-HT₆R ligands and ROCK I/II inhibitors.

Figure 12

Examples of ROCK I/ROCK II ligands: (A) mapped to the 5-HT₆R pharmacophore model; (B) docked to homology model of 5-HT₆R; (a) 31, (b) 44, (c) 32.

Figure 13

Examples of inhibitors of CDK5 with their affinities (IC₅₀ or K_i) within group (a–d) 45 [131], 46 [131], 47 [131], 48 [132], 49 [133], 50 [134], 51 [135], 52 [136], 53 [136], 54 [137], 55 [138], 44 (CHEMBL1988581).

Figure 14

(a) 2D protein-ligand interactions for roscovitine—strong CDK5 inhibitor (generated using Schrodinger Suite); (b) The examples of structural fragments of 5-HT₆R ligands favorable for interactions with Cys83 in ATP binding pocket of CDK5.

Figure 15

Examples of CDK5 ligands which were not successfully mapped to the 5-HT₆R pharmacophore model.

Figure 16

Examples of CDK5 ligands which were successfully mapped to the 5-HT₆R pharmacophore model (A) together with their docking results (B); (a) 44, (b) 47.