The study of natural products as potential drug leads has gained tremendous research interest. Quercetin is one of those natural products. It belongs to the family of flavonoids and, more specifically, flavonols. This review summarizes the beneficial pharmaceutical effects of quercetin, such as its anti-cancer, anti-inflammatory, and antimicrobial properties, which are some of the quercetin effects described in this review. Nevertheless, quercetin shows poor bioavailability and low solubility. For this reason, its encapsulation in macromolecules increases its bioavailability and therefore pharmaceutical efficiency. In this review, a brief description of the different forms of encapsulation of quercetin are described, and new ones are proposed. The beneficial effects of applying new pharmaceutical forms of nanotechnology are outlined.

It is well-known that monoamine oxidase (MAO) plays a pivotal role in neurodegeneration and the inhibition of this enzyme can manifest antidepressant properties as well as have a positive impact in Alzheimer’s and Parkinson’s diseases. MAO has two isoforms: MAO-A and MAO-B. The main hMAO-B inhibitors used for the treatment of Alzheimer’s and Parkinson’s diseases, encompass a terminal triple bond in their structure, which provides their potency. Recently, a new class of inhibitors has emerged, bearing the carbon–carbon triple bond not necessarily at the end of the chain. In this review, the structure and physiological function of the MAO enzymes is discussed, the general synthetic procedures of propargylamines, as well as their mechanism of inhibition. Moreover, it is highlighted the current development and discovery of potential hMAO-B inhibitors from propargylamine scaffolds, showcasing their structure–activity relationships (SARs) with the enzyme. Conformational relationships’ analysis is performed as well. Induced fit docking is performed, also, to the most potent compounds revealed in order to assess their binding energy and interactions with the enzyme. Finally, molecules which do not contain a propargylamine moiety in their structure were studied and compared against a known hMAO-B inhibitor, deprenyl. From the superimposition results of these molecules with deprenyl, as well as the interactions of the molecules with the amino acids of the active site of hMAO-B, it appears that these compounds have several similarities with deprenyl, opening new paths for the creation of novel molecules against Alzheimer’s disease (AD).

The arachidonic acid pathway plays a pivotal role in the biosynthesis of important inflammatory and signal transducing agents such as prostaglandins, leukotrienes and thromboxanes. When this pathway is deregulated, it leads to pathological conditions such as cardiovascular diseases, metabolic diseases, and cancer. Two key enzymes of the pathway are cyclooxygenases (COXs) and lipoxygenases (LOXs), which are responsible for the production of prostaglandins and leukotrienes, respectively. Consequently, these enzymes have long been recognized as key therapeutic targets for the treatment and management of inflammatory disorders and other pathological conditions associated with inflammation. In this review, we describe the new evidence over the last 4 years regarding the arachidonic acid pathway. Moreover, we will pay attention to the structure and function of the COX-2 and 5-LOX enzymes and their role in inflammation, as well as define their active sites. Later, we will discuss the most potent, dual inhibitors of COX-2 and 5-LOX enzymes, based on in vitro and in vivo experiments, from 2020–2024. Structure–activity relationship (SAR) analysis of these compounds revealed four key structural features required for potent dual inhibition of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX). We refer to these criteria as “The Rule of Four for Inflammation”.

Cardiometabolic diseases (CVDs) are the leading cause of premature mortality and disability worldwide, arising from of cardiovascular and metabolic dysregulation. This review focuses on six critical therapeutic targets established in cardiometabolic regulation: GLP-1R, GIPR, FGFR1/β-Klotho, PCSK9, NF-κB, and the NLRP3 inflammasome. Drawing on curated structural datasets, we analyze the mechanisms of action and map key binding domain features that govern ligand efficacy and specificity. Dual GLP-1R/GIPR agonists, such as tirzepatide, demonstrate superior outcomes in glycemic control and weight reduction. Concurrently, inhibiting PCSK9, NF-κB, and NLRP3 helps to lower cholesterol and reduce harmful inflammation, offering cardioprotection. Structural analysis across these targets reveals complementary motifs (aromatic, hydrophobic, and polar residues). These insights guide the rational design of next-generation multi-target ligands (molecules capable of modulating two or more biological targets involved in related disease pathways, producing integrated therapeutic effects). Such integrated agents are promising for providing combined cardiovascular and metabolic benefits, thus reducing the risks associated with complex therapeutic drug combinations.

The renin–angiotensin–aldosterone system (RAAS) is essential for controlling blood pressure and maintaining fluid balance, driving significant structural changes throughout the cardiovascular system, including the heart and blood vessels. As a result, the RAAS is a key therapeutic target for various chronic cardiovascular diseases, ranging from arterial hypertension (AH) to heart failure (HF). In this review, one of our objectives is to describe the new evidence over the last 4 years regarding the RAAS. Moreover, we pay attention to the structure and function of the angiotensin II type 1 receptor (AT1R) and its role in hypertension, as well as define its active site. Later, we discuss the most potent, selective inhibitors of AT1 receptors, based on in vitro and in vivo experiments, from 2020 to 2024. Large peptide molecules, small non-peptide-like molecules, and sartan derivatives are analyzed. The low IC₅₀ values of the entities that do not resemble sartans showcase the vast chemical space that can be explored for the creation of more potent antihypertensive medications. We have also employed computational chemistry tools in order to identify key molecular interactions between the compounds of the literature studied in order to elucidate the underlying reasons why these different molecules exhibit variations in their binding energies and overall potency.

Renin, a key aspartic protease central to the renin–angiotensin–aldosterone system (RAAS), remains a therapeutic target for hypertension despite the withdrawal of the only approved direct renin inhibitor, Aliskiren, due to unfavorable drug–drug interactions and safety concerns. Here, we report a computational protein design-driven evaluation of (S)-3-((3-(1H-imidazol-1-yl)propyl)amino)-2-(((S)-1-carboxy-2-(cyclooctanecarboxamido)ethyl)amino)-3-oxopropanoic acid (N-CDAH), a novel lipophilic cyclooctanoyl- derivative, as a next-generation renin inhibitor scaffold. This scaffold was designed based on the rationale of leveraging the carnosine like backbone while optimizing lipophilicity and metabolic stability. Pharmacokinetic, ADME, and toxicity predictions (SwissADME, pkCSM) revealed greater predicted aqueous solubility, enhanced metabolic stability, and significantly reduced off-target liabilities compared with Aliskiren (specifically, non-inhibition of major CYP isoforms). Molecular docking (AutoDock Vina binding affinity: −8.08 kcal/mol; Maestro Induced Fit Docking score: −11.149 kcal/mol) and molecular dynamics simulations confirmed favorable binding interactions, conformational adaptability, and complex stability within the renin active site. To contextualize its performance within the broader chemical space, the diastereomeric analog of N-CDAH as well as structurally related compounds identified through SwissSimilarity were also examined using computational workflow. The MD analysis (200 ns) demonstrated that the inhibitor is anchored via a dual stabilization mechanism: hydrophobic enclosure coupled with persistent ionic interactions. These integrative in silico results highlight the potential of this derivative to overcome Aliskiren’s pharmacological shortcomings, providing a strong computational rationale for experimental validation and underscoring the role of structure-based drug design in antihypertensive drug discovery.