Current Drug Discovery Technologies - Volume 19, Issue 6, 2022

The proteinaceous nature of monoclonal antibodies (mAbs) makes them highly sensitive to various physical and chemical conditions, thus leading to instabilities that are classified as physical and chemical instabilities. In this review, we are discussing in detail the physical instability of mAbs because a large number of articles previously published solely focus on the chemical aspect of the instability with little coverage on the physical side. The physical instabilities of mAbs are classified into denaturation and aggregation (precipitation, visible and subvisible particles). The mechanism involved in their formation is discussed in the article, along with the pathways correlating the denaturation of mAb or the formation of aggregates to immunogenicity. Further equations like Gibbs-Helmholtz involved in detecting and quantifying denaturation are discussed, along with various factors causing the denaturation. Moreover, questions related to aggregation like the types of aggregates and the pathway involved in their formation are answered in this article. Factors influencing the physical stability of the mAbs by causing denaturation or formation of aggregates involving the structure of the protein, concentration of mAbs, pH of the protein and the formulations, excipients involved in the formulations, salts added to the formulations, storage temperature, light and UV radiation exposure and processing factors are mentioned in this article. Finally, the analytical approaches used for detecting and quantifying the physical instability of mAbs at all levels of structural conformation like far and near UV, infrared spectroscopy, capillary electrophoresis, LC-MS, microflow imagining, circular dichroism and peptide mapping are discussed.

Background: Alzheimer’s Disease (AD) is related to the total loss of presynaptic neurotransmitters of the cholinergic system in regions of the brain related to memory. Approximately 15% of the population beyond the age of 65 years are suffering from dementia due to AD and the rate is rising exponentially with age. Objective: The objective of this research was the synthesis of a series of 1-(4-substituted-2- thioxoquinolin-1(2H)-yl)-2-substituted ethanoneV (a-c(1-4)) by undergoing acetylation at the nitrogen of 4-hydroxyquinolin-2-(1H)-one and replacing its oxygen atom with sulphur moiety via the process of thionation. To carry out-docking studies of the title compounds were carried out using Molegro Virtual Docker (MVD-2013, 6.0) software and in-vitro screening of anti-alzheimer’s activity by Ellman assay method. Methods: The synthesis of the title compounds was carried out via the sequential reaction from the initial dianilide to ring closure to the substituted quinoline-2-ones using polyphosphoric acid as a cyclising agent. These substituted quinoline-2-ones on thionation by phosphorous pentasulphide in aluminium trioxide gave quinoline-2-thiones and on further condensation with chloroacetyl chloride, they resulted in compounds with a leaving group. Nucleophilic substitution reaction of chloroacetylquinoline- 2-thiones with secondary amines resulted in the title compounds 1-(4-substituted-2- thioxoquinolin-1(2H)-yl)-2-substituted ethanone V(a-c(1-4)). The pharmacophore mapping of synthesized compounds was performed by using Molegro Virtual Docker (MVD-2013,6.0). The title compounds were tested for their in vitro anti-Alzheimer's activity using the Ellman assay method. Results: All the synthesized compounds were characterized by IR, ¹H NMR, ¹³C NMR, and Mass spectral data. Docking studies of all the synthesized compounds were carried out using a structural mechanism for the inhibition of CDK5-p25 by roscovitine, aloisine, and indirubin (PDB ID: 1UNG), showed favourable results, with compound (Vb3) showing a MolDock score of -85.9788 that was comparable to that of the active ligand (ALH_1288 [B]) with MolDock score of - 87.7609. Conclusion: The synthesized derivatives possessed the potential to bind with some of the amino acid residues of the active site. Compound 2-(6-chloro-4-hydroxy-2-thioxoquinolin-1(2H)-yl-1-piperazin- 1-ethanone (Vb3) was found to be the most active among the synthesized derivatives, with IC50 values of 32 ± 0.1681. All the synthesized compounds showed potent to moderate activity in comparison to the reference standard donepezil.

Background: Glucosinolates (β-thioglucoside-N-hydroxysulfates) are a water-soluble organic anion with sulfur- and nitrogen-containing glycosides which are found in abundance in Cruciferous plants. Ergosterol (ERG13) lanosterol-14α-demethylase protein has been targeted for inhibition studies as a key regulator enzyme of fungal membrane biosynthesis. Objectives: To understand the molecular mechanism of inhibition of Ergosterol (ERG13) lanosterol- 14α-demethylase by various phytochemicals from brassicales, i.e., glucosinolates and their potential role as putative drug molecules. Methods: In this study, in silico analyses were performed to predict the molecular basis of various glucosinolates as a potential inhibitor of lanosterol-14α-demethylase protein, which is a key regulator of fungal membrane biosynthesis and its pharmacodynamics and toxicity profile. 3d structures of various glucosinolates were retrieved from PubChem, and the target protein, lanosterol-14α-demethylase (Pdb ID- 4lxj), was retrieved from the RCSB protein data bank. Molecular docking and interactions were carried out using the PyRx software using the AutoDOCK toolbar with default parameters. Dru- LiTo, ORISIS web servers were used to predict various drug likeliness predictions and Lipinski’s Rule of 5, whereas admetSAR was used for prediction of toxicity, and PASS Program was used to study the antifungal and antimicrobial properties of these compounds. Results: This study shows that among the different compounds screened, gluconasturtiin, Glucotropaeolin, and Indolylmethyl-Glucosinolate showed the highest binding energies of -8.7 kcal/mol, -8.5 kcal/mol, and -8.3 kcal/mol with the lanosterol-14α-demethylase, respectively. Further all the compounds follow the Lipinski’s rule as well as they are found to be non-carcinogenic and non-cytotoxic in nature. These compounds also show antifungal properties. Conclusion: This study thus reveals that various glucosinolates interact with the ERG13 enzyme at various amino acid positions, which behaves as a catalytic site, thus indicates the probable mechanism of inactivation, and subsequently, these can be used as potential drug molecules. In vitro studies can be taken to further examine the utility of these compounds as antifungal agents.

Nanomaterials are indeed a nanoscale technology that deals with the creation, evaluation, fabrication, and utilization of systems at the nanometre scale by manipulating their size and shape. We consider natural polysaccharides such as promising polysaccharides, which are biodegradable, nontoxic, abundant, and inexpensive bio-polymeric precursors for preparing the materials of choice in various industries. The aim is to review different methods to produce hydrophobically modified Abelmoschus esculentus nanoparticles and study the evaluation processes of these nanoparticles as given in the literature. It proved the benefits of derivatives of gum by introducing different chemical groups. The chemical functionalization of gum mainly includes the esterification, etherification, and crosslinking reactions of the hydroxyl groups and contains a special fibre which takes sugar levels in the blood under control, providing a sugar quantity suitable for the bowels. Okra contains mucilage that helps remove poisonous chemicals and bad cholesterol, often overloads the liver. Recovering from psychological conditions, like depression, general weakness, and joint healthiness can be done with Okra. Someone additionally applied it for pulmonary inflammation, bowel irritation, and sore throat. Purgative properties okra possesses are beneficial for bowel purification. It is used to counteract the acids. Fibre okra contains a valuable nutrient for intestinal microorganisms and ensures proper intestine functionality. It also protects the mucosa of the digestive tract by covering them with an extra layer because of its alkaline nature. Nanotechnology has emerged as a critical component of pharmaceutics, with many applications in drug carriers of interest aimed at improving drug clinical outcomes such as cancer, diabetes mellitus, wound care management, atopic dermatitis, cosmeceutical, etc. Beneficial outcomes of this review are discussed briefly.

Background: The continuous increase in mortality of breast cancer and other forms of cancer due to the failure of current drugs, resistance, and associated side effects calls for the development of novel and potent drug candidates. Methods: In this study, we used the QSAR and extreme learning machine models in predicting the bioactivities of some 2-alkoxycarbonylallyl esters as potential drug candidates against MDA-MB-231 breast cancer. The lead candidates were docked at the active site of a carbonic anhydrase target. Results: The QSAR model of choice satisfied the recommended values and was statistically significant. The R²pred (0.6572) was credence to the predictability of the model. The extreme learning machine ELM-Sig model showed excellent performance superiority over other models against MDAMB- 231 breast cancer. Compound 22 with a docking score of 4.67 kcal mol^-1 displayed better inhibition of the carbonic anhydrase protein, interacting through its carbonyl bonds. Conclusion: The extreme learning machine’s ELM-Sig model showed excellent performance superiority over other models and should be exploited in the search for novel anticancer drugs.

Background: Various medications, surgeries, and assisted reproductive techniques are used to treat male infertility, but the high cost and low effectiveness have made these methods unpopular. The use of herbal medicines such as Withania somnifera, Ceratonia siliqua, Nigella sativa and Alpinia officinarum for the treatment of male infertility has become highly popular in recent years. Objective: We conducted this systematic review to evaluate the recent scientific evidence regarding herbal medicines used to treat idiopathic male infertility (IMI). Methods: Online literature resources were checked using different search engines, including ISI, Web of Knowledge, Medline, PubMed, Scopus, and Google Scholar. Date restrictions were applied to 2020, and the publication language was restricted to English and Persian. The risk of bias was evaluated using the Cochrane method. Results: Out of 851 articles, 14 trials with 1218 participants were included. Of the 15 plants and medicinal products introduced in the selected studies, 12 cases were effective in treating male infertility. Each of these plants or products affects specific components of male fertility for which various mechanisms were mentioned, but most of them had antioxidant effects. No serious side effects were reported. Conclusion: Whitania somnifera roots, Alpinia officinarum, Nigella sativa seeds, Tomato, and Ceratonia siliqua and the formulation of Xperm, PHF, Churna Ratnam, Svaguptadi Churna, Y virilin capsule, manix capsule, and Tradafertil tablet revealed successful outcomes in treatment of idiopathic male infertility.