The protozoan diseases Human African Trypanosomiasis (HAT), Chagas disease (CD), and leishmaniases span worldwide and therefore their impact is a universal concern. The present regimen against kinetoplastid protozoan infections is poor and insufficient. Target-based design expands the horizon of drug design and development and offers novel chemical entities and potential drug candidates to the therapeutic arsenal against the aforementioned neglected diseases. In this review, we report the most promising targets of the main kinetoplastid parasites, as well as their corresponding inhibitors. This overview is part of the Special Issue, entitled “Advances of Medicinal Chemistry against Kinetoplastid Protozoa (Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp.) Infections: Drug Design, Synthesis and Pharmacology”.

In this in silico study, we conducted an in-depth exploration of the potential of natural products and antihypertensive molecules that could serve as inhibitors targeting the key proteins of the SARS-CoV-2 virus: the main protease (Mpro) and the spike (S) protein. By utilizing Induced Fit Docking (IFD), we assessed the binding affinities of the molecules under study to these crucial viral components. To further comprehend the stability and molecular interactions of the “protein-ligand” complexes that derived from docking studies, we performed molecular dynamics (MD) simulations, shedding light on the molecular basis of potential drug candidates for COVID-19 treatment. Moreover, we employed Molecular Mechanics Generalized Born Surface Area (MM-GBSA) calculations on all “protein-ligand” complexes, underscoring the robust binding capabilities of rosmarinic acid, curcumin, and quercetin against Mpro, and salvianolic acid b, rosmarinic acid, and quercetin toward the S protein. Furthermore, in order to expand our search for potent inhibitors, we conducted a structure similarity analysis, using the Enalos Suite, based on the molecules that indicated the most favored results in the in silico studies. The Enalos Suite generated 115 structurally similar compounds to salvianolic acid, rosmarinic acid, and quercetin. These compounds underwent IFD calculations, leading to the identification of two salvianolic acid analogues that exhibited strong binding to all the examined binding sites in both proteins, showcasing their potential as multi-target inhibitors. These findings introduce exciting possibilities for the development of novel therapeutic agents aiming to effectively disrupt the SARS-CoV-2 virus lifecycle.

Multiple sclerosis (MS) is a serious central nervous system (CNS) disease responsible for disability problems and deterioration of the quality of life. Several approaches have been applied to medications entering the market to treat this disease. However, no effective therapy currently exists, and the available drugs simply ameliorate the destructive disability effects of the disease. In this review article, we report on the efforts that have been conducted towards establishing the conformational properties of wild-type myelin basic protein (MBP), myelin proteolipid protein (PLP), myelin oligodendrocyte glycoprotein (MOG) epitopes or altered peptide ligands (ALPs). These efforts have led to the aim of discovering some non-peptide mimetics possessing considerable activity against the disease. These efforts have contributed also to unveiling the molecular basis of the molecular interactions implicated in the trimolecular complex, T-cell receptor (TCR)–peptide–major histocompatibility complex (MHC) or human leucocyte antigen (HLA).

Antagonists of the AT1receptor (AT1R) are beneficial molecules that can prevent the peptide hormone angiotensin II from binding and activating the specific receptor causing hypertension in pathological states. This review article summarizes the multifaced applications of solid and liquid state high resolution nuclear magnetic resonance (NMR) spectroscopy in antihypertensive commercial drugs that act as AT1R antagonists. The 3D architecture of these compounds is explored through 2D NOESY spectroscopy and their interactions with micelles and lipid bilayers are described using solid state ¹³CP/MAS, ³¹P and ²H static solid state NMR spectroscopy. Due to their hydrophobic character, AT1R antagonists do not exert their optimum profile on the AT1R. Therefore, various vehicles are explored so as to effectively deliver these molecules to the site of action and to enhance their pharmaceutical efficacy. Cyclodextrins and polymers comprise successful examples of effective drug delivery vehicles, widely used for the delivery of hydrophobic drugs to the active site of the receptor. High resolution NMR spectroscopy provides valuable information on the physical-chemical forces that govern these drug:vehicle interactions, knowledge required to get a deeper understanding on the stability of the formed complexes and therefore the appropriateness and usefulness of the drug delivery system. In addition, it provides valuable information on the rational design towards the synthesis of more stable and efficient drug formulations.

The structure assignment and conformational analysis of the thiosemicarbazones, DKI21 and DKI24, were performed through homonuclear and heteronuclear 2D Nuclear Magnetic Resonance (NMR) spectroscopy (2D-COSY, 2D-NOESY, 2D-ROESY, 2D-HSQC, and 2D-HMBC) and quantum mechanics (QM) calculations, using Functional Density Theory (DFT). In addition, utilizing a combination of 2D-NOESY and 2D-ROESY spectra an exo structure was established for both of the analogs. This experimental results were confirmed by theoretical mechanistic studies, as the lowest minima conformations derived through DFT calculations were compatible with the spatial correlations observed in the 2D-NOESY and 2D-ROESY spectra. Finally, molecular binding experiments were performed to detect the potential targets for DKI21 and DKI24, derived from SwissAdme. In silico molecular binding experiments showed favorable binding energy values for the most of the enzymes studied. The ADMET calculations, using the preADMET and pKCSm software, showed that the two molecules appear as possible drug leads.