Current Topics in Medicinal Chemistry - Volume 23, Issue 1, 2023

The new pandemic caused by the coronavirus (SARS-CoV-2) has become the biggest challenge that the world is facing today. It has been creating a devastating global crisis, causing countless deaths and great panic. The search for an effective treatment remains a global challenge owing to controversies related to available vaccines. A great research effort (clinical, experimental, and computational) has emerged in response to this pandemic, and more than 125000 research reports have been published in relation to COVID-19. The majority of them focused on the discovery of novel drug candidates or repurposing of existing drugs through computational approaches that significantly speed up drug discovery. Among the different used targets, the SARS-CoV-2 main protease (M^pro), which plays an essential role in coronavirus replication, has become the preferred target for computational studies. In this review, we examine a representative set of computational studies that use the M^pro as a target for the discovery of small-molecule inhibitors of COVID-19. They will be divided into two main groups, structure-based and ligand-based methods, and each one will be subdivided according to the strategies used in the research. From our point of view, the use of combined strategies could enhance the possibilities of success in the future, permitting to development of more rigorous computational studies in future efforts to combat current and future pandemics.

Scutellaria baicalensis georgi, known as “Huangqin” in its dried root form, is a herb widely used in traditional Chinese medicine for “clearing away heat, removing dampness, purging fire and detoxification”. Baicalin, baicalein, wogonin, and wogonoside are the main flavonoid compounds found in Scutellaria baicalensis. Scutellaria baicalensis flavonoid components have the potential to prevent and treat a host of diseases. The components of S. baicalensis have limited clinical application due to their low water solubility, poor permeability, and microbial transformation in vivo. Nanopharmaceutical techniques can improve their biopharmaceutical properties, enhance their absorption in vivo, and improve their bioavailability. However, due to the limited number of clinical trials, doubts remain about their toxicity and improvements in human absorption as a result of nanoformulations. This review summarizes the latest and most comprehensive information regarding the absorption, distribution, metabolism, and excretion of the Scutellaria baicalensis components in vivo. We examined the main advantages of nanodrug delivery systems and collected detailed information on the nanosystem delivery of the Scutellaria baicalensis components, including nanosuspensions and various lipid-based nanosystems. Lipid-based systems including liposomes, solid lipid nanoparticles, nanoemulsions, and self-micro emulsifying drug delivery systems are introduced in detail. In addition, we make recommendations for related and future research directions. Future research should further examine the absorption mechanisms and metabolic pathways of nanoformulations of the components of Scutellaria baicalensis in vivo, and accurately track the in vivo behavior of these drug delivery systems to discover the specific reasons for the enhanced bioavailability of nanoformulations of the scutellaria baicalensis components. The development of targeted oral administration of intact nanoparticles of Scutellaria baicalensis components is an exciting prospect.

Skin cancer, including basal cell carcinoma, melanoma, and squamous cell carcinoma, is conventionally treated by surgery, phototherapy, immunotherapy, and chemotherapy. For decades, surgical removal of malignant cancers has favored patients' therapeutic options. However, multiple aspects, such as the patient's comorbidities, the anatomical location of the lesion, and possible resistance to recurrent excisions, can influence the decision to conduct surgery. Therefore, topical and transdermal therapy may be a more appropriate option, allowing for higher therapeutic levels at the site of action and reducing toxicity than systemic therapy. The most commonly used topical agents for treating skin carcinoma are- 5-fluorouracil, imiquimod, sonidegib, dacarbazine, etc. However, physicochemical drug characteristics and skin physiological barriers limit the anticancer potency of topical as well as transdermal drug delivery. In recent years, unquestionable signs of progress have been demonstrated to circumvent these challenges. In particular, significant studies have been made, including modification of bio-actives, permeability enhancers, incorporation of advanced nano and microcarriers, and physical enhancement devices. This critical review summarizes the advancement in the chemical composition of bioactives used in skin cancer, such as sinecatechins, BIL-010t, patidegib, gingerol, curcumin, remetinostat, epigallocatechin-3-gallate, etc. Furthermore, this review specifically addresses the progress in transdermal delivery systems for melanoma and nonmelanoma cancer therapy, emphasizing advances in physical and chemical penetration enhancement and nanocarrier-assisted transdermal systems.

The application of nanoparticles in medication delivery has revolutionized the field of therapeutic biology. To improve medical efficacy, currently, drug nanocarriers are employed to control the release and stability, expand its circulation time, or protect it from cell clearance or premature breakdown. A crosslinked polymeric framework is used to crosslink the hydrogel nanoparticle dispersions for safer and stable delivery on target sites. Nanogels have developed in the last two decades as potential biomaterials with a wide variety of applications. Later attributes of nanogels are mainly due to large surface areas, retention of molecules, size flexibility, and water-based formulations that have made them popular as drug delivery vehicles, as seen by several in vivo uses. The gel matrix containing the nanoparticle drug demonstrated a considerable increase in drug penetration in transdermal drug and topical delivery methods. This review aims to understand why and how nanogels are considered so innovative as a drug delivery method. It also examines their preparation methods and applications in the pharmaceutical and biomedical fields and discusses the benefits of nanogels, including swelling capacity and stimulus stimuli sensitivity. Nanogels, on the other hand, have recently been investigated for applications outside the field of biomedicine. Since there are many possible uses for nanogels, we have comprehensively reviewed the current state of the art for all feasible nanogel applications and manufacturing methods.

Background: Herein, molecular docking approaches and DFT ab initio simulations were combined for the first time, to study the key interactions of cyclodextrins (CDs: α-CD, β-CD, and γ-CD) family with potential pharmacological relevance and the multidrug resistance P-gp protein toward efficient drug-delivery applications. The treatment of neurological disorders and cancer therapy where the multiple drug-resistance phenomenon mediated by the P-gp protein constitutes the fundamental cause of unsuccessful therapies. Objectives: To understand more about the CD docking mechanism and the P-gp. Methods: In order to achieve the main goal, the computational docking process was used. The observed docking-mechanism of the CDs on the P-gp was fundamentally based on hybrid backbone/side-chain hydrophobic interactions,and also hybrid electrostatic/side-chain interactions of the CD-ligands' OHmotifs with acceptor and donor characteristics, which might theoretically cause local perturbations in the TMD/P-gp inter-residues network, influencing ligand extrusion through the blood-brain barrier. P-gp residues were conformationally favored. Despite the structural differences, all the cyclodextrins exhibit very close Gibbs free binding energy values (or affinity) by the P-gp binding site (transmembrane domains - TMDs). Result: The obtained theoretical docking-mechanism of the CDs on the P-gp was fundamentally based on hybrid backbone/side-chain hydrophobic interactions, and also hybrid electrostatic/side-chain interactions of the OH-motifs of the CD-ligands with acceptor and donor properties which theoretically could induce allosteric local-perturbations in the TMDs-inter-residues network of P-gp modulating to the CD-ligand extrusion from the blood-brain-barrier (or cancer cells). Conclusion: Finally, these theoretical results open new horizons for evaluating new nanotherapeutic drugs with potential pharmacological relevance for efficient drug-delivery applications and precision nanomedicine.