Neurodegenerative diseases (NDD) have been of great interest to scientists for a long time due to their multifactorial character. Among these pathologies, Alzheimer’s disease (AD) is of special relevance, and despite the existence of approved drugs for its treatment, there is still no efficient pharmacological therapy to stop, slow, or repair neurodegeneration. Existing drugs have certain disadvantages, such as lack of efficacy and side effects. Therefore, there is a real need to discover new drugs that can deal with this problem. However, as AD is multifactorial in nature with so many physiological pathways involved, the most effective approach to modulate more than one of them in a relevant manner and without undesirable consequences is through polypharmacology. In this field, there has been significant progress in recent years in terms of pharmacoinformatics tools that allow the discovery of bioactive molecules with polypharmacological profiles without the need to spend a long time and excessive resources on complex experimental designs, making the drug design and development pipeline more efficient. In this review, we present from different perspectives how pharmacoinformatics tools can be useful when drug design programs are designed to tackle complex diseases such as AD, highlighting essential concepts, showing the relevance of artificial intelligence and new trends, as well as different databases and software with their main results, emphasizing the importance of coupling wet and dry approaches in drug design and development processes.

Atrial fibrillation (AF) involves electrical remodeling of the atria, with ion channels such as Na_V1.5, K_V1.5, and TASK-1 playing crucial roles. This study investigates acetamide-based compounds designed as multi-target inhibitors of these ion channels to address AF. Compound 6f emerged as the most potent in the series, demonstrating a strong inhibition of TASK-1 (IC₅₀ ∼0.3 μM), a moderate inhibition of Na_V1.5 (IC₅₀ ∼21.2 μM) and a subtle inhibition of K_V1.5 (IC₅₀ ∼81.5 μM), alongside unexpected activation of TASK-4 (∼40% at 100 μM). Functional assays on human atrial cardiomyocytes from sinus rhythm (SR) and AF patients revealed that 6f reduced action potential amplitude in SR (indicating Na_V1.5 block), while in AF it increased action potential duration (APD), reflecting high affinity for TASK-1. Additionally, 6f caused hyperpolarization of the resting membrane potential in AF cardiomyocytes, consistent with the observed TASK-4 activation. Mathematical modeling further validated its efficacy in reducing AF burden. Pharmacokinetic analyses suggest favorable absorption and low toxicity. These findings identify 6f as a promising multi-target therapeutic candidate for AF management.

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Its treatment includes antiarrhythmic drugs (AADs) to modulate the function of cardiac ion channels. However, AADs have been limited by proarrhythmic effects, non-cardiovascular toxicities as well as often modest antiarrhythmic efficacy. Theoretical models showed that a combined blockade of Na_v1.5 (and its current, I_Na) and K_v1.5 (and its current, I_Kur) ion channels yield a synergistic anti-arrhythmic effect without alterations in ventricles. We focused on K_v1.5 and Na_v1.5 to search for structural similarities in their binding site (BS) for flecainide (a common blocker and widely prescribed AAD) as a first step for prospective rational multi-target directed ligand (MTDL) design strategies. We present a computational workflow for a flecainide BS comparison in a flecainide-K_v1.5 docking model and a solved structure of the flecainide-Na_v1.5 complex. The workflow includes docking, molecular dynamics, BS characterization and pattern matching. We identified a common structural pattern in flecainide BS for these channels. The latter belongs to the central cavity and consists of a hydrophobic patch and a polar region, involving residues from the S6 helix and P-loop. Since the rational MTDL design for AF is still incipient, our findings could advance multi-target atrial-selective strategies for AF treatment.

Atrial fibrillation (AF) is the most common cardiac arrhythmia. Its treatment includes antiarrhythmic drugs (AADs) to modulate the function of cardiac ion channels. However, AADs have been limited by proarrhythmic effects, non-cardiovascular toxicities as well as often modest antiarrhythmic efficacy. Theoretical models showed that combined blockade of Nav1.5 (and its current INa) and Kv1.5 (and its current, IKur) ion channels yield a synergistic anti-arrhythmic effect without effect on ventricles. We focused on Kv1.5 and Nav1.5 to search for structural similarities in their binding site (BS) for flecainide (a common blocker and widely prescribed AAD), as a first step for prospective rational multi-target directed ligand (MTDL) design strategies. We presented a computational workflow for flecainide BS comparison in a flecainide-Kv1.5 docking model and a solved structure of flecainide-Nav1.5 complex. The workflow includes docking, molecular dynamics, BS characterization and pattern matching. We identified a common structural pattern in flecainide BS for these channels. The latter belongs to the inner cavity and consist of a hydrophobic patch and a polar region, involving residues from S6 helix and P-loop. Since the rational MTDL design for AF is still incipient, our findings could advance multi-target atrial-selective strategies for AF treatment.

During atrial fibrillation (AF), electrical remodeling occurs, involving ion channels like NaV1.5, KV1.5, and TASK-1. A promising AF treatment encompasses inhibiting these channels. In this study, acetamide compounds were designed based on the local anesthetic pharmacophore as potential NaV1.5, KV1.5, and TASK-1 inhibitors. Compound 6f emerged as the most potent in the series, with IC50 values determined in Xenopus oocytes of approximately 0.3 µM in TASK-1, 81.5 µM in KV1.5, and 21.2 µM in NaV1.5. Unexpectedly, 6f activated at 100 µM another cardiac K2P channel (TASK-4) by about 40%. Next, we performed patch clamp experiments of human atrial cardiomyocytes from sinus rhythm (SR) or AF patients. In SR 6f reduced action potential amplitude (indicating NaV1.5 block) while in AF it increased action potential duration (APD), reflecting high affinity for TASK-1. Additionally, a hyperpolarization in resting membrane potential occurred in AF cardiomyocytes by 6f, consistent with the TASK-4 activation we observed. In a mathematical whole-atria model, 6f prolonged APD and tissue refractoriness, proving efficacious both for AF prevention and cardioversion. Favorable pharmacokinetic properties of 6f in silico, including good absorption and low toxicity, as well as its lack of cytotoxicity in a hemolytic assay, suggest its potential as an AF treatment.