Letters in Drug Design & Discovery - Volume 20, Issue 3, 2023

The utilization of biomaterials in the human body was first practiced several years ago to restore normal functional activities by replacing the impaired organs with bio-inspired materials without devastating the cells and tissues. Today, many advanced technologies are reported to be worthwhile to effectively prepare different categories of biomaterials with amplified properties and characteristics for therapeutic applications. When considering the prosperous aspects of biomaterials, keratin has proved to be a fascinating material and has allured many researchers in various novel scientific studies, especially in drug delivery systems. Keratin is a naturally derived fibrous protein with cysteine, proline, serine, and glycine as the main amino acid constituents and has been found to have remarkable properties. Although keratin exhibits excellence and loss of distinction, it is utilized effectively in drug delivery for treating various diseases. Certainly, keratin nanoparticles (KNPs) showed remarkable features, such as optimistic surface area, good encapsulation efficiency, and controlled release of drugs. However, there is a need for more research to know about the cell interaction with keratin nanoparticles in novel drug delivery management. Indeed, certain biological and mechanical factors in alpha and beta keratins are still ambiguous, and higher attentiveness is required. The major purpose of this review is to assess the prospective utility and outstanding features of keratin nanoparticles in drug delivery systems. Keratin types, source of extraction, and properties are reviewed in this article. The characteristics and development of KNP are highlighted. Furthermore, the importance of nanoparticles in drug delivery, drug release mechanisms, challenges, and the need for future research are discussed.

Background: Even with the massive increase in financial investments in pharmaceutical research over the last decade, the number of new drugs approved has plummeted. As a result, finding new uses for approved pharmaceuticals has become a prominent alternative approach for the pharmaceutical industry. Objective: Drug repurposing or repositioning is a game-changing development in the field of drug research that entails discovering additional uses for previously approved drugs. Methods: In comparison to traditional drug discovery methods, drug repositioning enhances the preclinical steps of creating innovative medications by reducing the cost and time of the process. Drug repositioning depends heavily on available drug-disease data, so the fast development of available data as well as developed computing skills has resulted in the boosting of various new drug repositioning methods. The main goal of this article is to describe these different methods and approaches for drug repurposing. Results: The article describes the basic concept of drug repurposing, its significance in discovering new medications for various disorders, drug repurposing approaches such as computational and experimental approaches, and previous as well as recent applications of drug repurposing in diseases such as cancer, COVID-19, and orphan diseases. Conclusion: The review also addresses obstacles in drug development using drug repurposing strategies, such as a lack of financing and regulatory concerns and concludes with outlining recommendations for overcoming these challenges.

Objective: Thymus transcaspicus (Lamiaceae) is an Iranian species of Thymus, and Ungernia trisphaera Bunge belongs to the family Amaryllidaceae. Cytotoxic properties of total ethanolic extract of T. transcaspicus and U. trisphaera were investigated against different cell lines including B16F10, PC3, U87, and MCF-7. Methods: The proliferation, cell cycle, and migration of the cells were determined by thiazolyl blue tetrazolium bromide (MTT) test, propidium iodide (PI) staining, and scratch assay respectively. The effects of U. trisphaera extract (UTE) on the activity of matrix metalloproteinases (MMPs) and angiogenesis were evaluated by the gelatin zymography method and chicken chorioallantoic membrane model, respectively. The GSH, SOD, and MDA were evaluated by colorimetric method. Results: The results showed that UTE could inhibit the development of malignant cells in a concentration- dependent manner, while the inhibitory effect of T. transcaspicus extract (TTE) was not significant compared to the control group. The UTE-induced sub-G1 peak apoptosis compared to the control group indicated that apoptotic cell death is involved in UTE-induced cytotoxicity. MMPs activity was significantly decreased 48 hours after treatment. Moreover, GSH level and SOD activity were significantly decreased while MDA and ROS levels were significantly increased after 24 hours treatment. In addition, combination of UTE (1.5-25 μg/mL) with doxorubicin (6 μg/mL) showed an additive cell growth inhibitory effect. Conclusion: UTE demonstrated cytotoxic and apoptogenic effects in different cancer cell lines, and it was found that apoptosis plays a crucial role in the cytotoxicity of UTE. Thus, U. trisphaera can be considered a potential medicinal herb in cancer treatment after comprehensive pharmacological and toxicological studies.

Background: Kelch-like protein 22 (KLHL22) was a newly discovered proto-oncogene and it is highly expressed in multiple breast cancer cell lines. Inhibition of KLHL22 can induce autophagy in tumor cells by regulating the mTORC1 pathway. Methods: In this study, the structure of the KLHL22 protein was predicted by homology modelling. The model was evaluated by Ramachandran Plot and Profile-3D. Virtual screening of a drug-like small molecule library of 400,000 compounds was performed, and six potentially active compounds were obtained. Results: Among them, compound 1 had the best docking posture with docking energy of -8.42 kcal/mol. Therefore, we further modified the structure of compound 1. 12 unreported compounds with lower docking energies were obtained. The results of ADMET prediction performed on them showed good druggability. The 60 ns molecular dynamics simulations were performed for compounds 1 and 10. MD studies showed that the complexes had stable RMSD, and the compounds formed good H-bonds interactions with essential amino acids (ASP64, TRP192). Conclusion: These results may provide new insights into the design and development of potent novel KLHL22 inhibitors.

Aim: Frequent use of antibiotics is responsible for the development of antibiotic resistance; thus, there is an urgent need for the development of new antibacterial agents that act by novel mechanism pathways. Objective: The aim of the study was to develop hybrid novel 4-aminoquinoline 1,3 5-triazine derivatives and determine their antibacterial activity. Methods: Novel hybrid 4-aminoquinoline 1,3,5-triazine derivatives were synthesized by nucleophilic substitution and characterized by different spectroscopic methods. Furthermore, in silico study was carried out with 16S-rRNA A-site (PDB id: 1J7T using Discovery Studio 2018 software) to exemplify key structural interactions. In vitro antibacterial activity of target compounds was evaluated against three Gram-positive and three Gram-negative bacterial strains. Results: In silico results have shown compound 8c to have both hydrophobic interactions (conventional hydrogen bond interactions with A A:16, A A:17 and carbon hydrogen bond with U A:14, G A:15) and hydrophilic interactions (G A:18G A:13, G A:15 and U A:19) along with excellent CDocker energy (- 28.2942). In vitro antibacterial results revealed that compound 8c showed better zone of inhibition against S. aureus (gram-positive) and E. coli (gram-negative) as compared to standard drug Cefixime. Conclusion: Our study demonstrated that in silico study supported the experimental study, and the developed 1,3,5-triazine-4-aminoquinoline derivatives may be used as potential leads for future antibacterial drug development.

Background: Plasmodium falciparum dihydroorotate dehydrogenase (PfDODH) is one of the enzymes currently explored in the treatment of malaria. Although there is currently no clinically approved drug targeting PfDODH, many of the compounds in clinical trials have [1, 2, 4,] triazolo [1, 5-a] pyrimidin- 7-amine backbone structure. Objective: This study sought to design new compounds from the fragments of known experimental inhibitors of PfDODH. Methods: Nine experimental compounds retrieved from Drug Bank online were downloaded and broken into fragments using the Schrodinger power shell; the fragments were recombined to generate new ligand structures using the BREED algorithm. The new compounds were docked with PfDODH crystal structure, after which the compounds were filtered with extensive drug-likeness and toxicity parameters. A 2D-QSAR model was built using the multiple linear regression method and externally validated. The electronic properties of the compounds were calculated using the density functional theory method. Results: Structural investigation of the six designed compounds, which had superior binding energies than the standard inhibitors, showed that five of them had [1, 2, 4,] triazolo [1, 5-a] pyrimidin-7-amine moieties and interacted with essential residues at the PfDODH binding site. In addition to their drug-like and pharmacokinetic properties, they also showed minimal toxicities. The externally validated 2D-QSAR model with R² and Q² values of 0.6852 and 0.6691 confirmed the inhibitory prowess of these compounds against PfDODH. The DFT calculations showed regions of the molecules prone to electrophilic and nucleophilic attacks. Conclusion: The current study thus provides insight into the development of a new set of potent PfDODH inhibitors.

Background: Bacterial infections caused by multidrug-resistant bacteria have emerged as major threats to human communities worldwide. There is a great need to develop new mechanisms by which anti-bacterial agents can combat bacterial antibiotic resistance. Objective: This study aims to synthesize and characterize a series of novel tetrahydrobenzothiophene derivatives and evaluate their anti-bacterial activities. Methods: In this study, we have synthesized 2-benzamido-4,5,6,7-tetrahydrobenzo[b]thiophene-3- carboxylic acid derivatives (3a-3r) and investigated their anti-bacterial activities against E. coli, P. aeruginosa, Salmonella, and S. aureus. Results: The MIC values demonstrated that all synthesized derivatives possessed potent anti-bacterial activity properties. Compounds 3b, 3e, 3f, 3g, 3h, 3n, and 3q exhibited in vitro excellent anti-bacterial efficiency. Compounds 3b, 3e, 3f, and 3p were evaluated by in vitro time-kill assay; they displayed concentration- dependent bacteriostatic effects. Compounds 3b, 3e, 3f, and 3p showed moderate water solubility, high stability in plasma, and moderate acute oral toxicity. Conclusion: Most of the 2-benzamido-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxylic acid derivatives exhibited potent anti-bacterial activities. The data reported in this paper may guide the design of tetrahydrobenzothiophene derivatives.

Background: Trihexyphenidyl chloride (THP) is an antidyskinetic medication used in single and combination therapy to symptomatically treat Parkinson's disease. Due to its fast metabolism and short elimination of half-life, it causes changes in plasma concentrations and requires frequent dosage. Objective: The aim of this study was to prepare a sustained release formulation of Trihexyphenidyl chloride (THP). Materials and Methods: Using chitosan as the natural polymer, the polymeric nanoparticles were prepared by using the ionic gelation method. A 3² response surface methodology was used to optimize the effects of independent variables, such as the amount of polymer (X1mg) and the amount of copolymer (X2mg), on dependent variables, such as entrapment efficiency (% EE) (Y1) and drug release (% DR) (Y2). Results: The prepared formulations were evaluated for Fourier transform-infrared (FTIR), X-ray Diffraction, Field scanning micrographs (FESEM), and In vitro drug release. Higher drug entrapment efficiency was observed for batch T11. FTIR confirmed the loading of trihexyphenidyl drug into the chitosan matrix. X-ray diffraction pattern indicated that the degree of crystallinity of pure drug was reduced in the formulated NPs. Conclusion: The drug release from the formulated batches (T1-T13) showed sustained-release action for around 9-14 hrs. The technique reduced the dosing frequencies and possible side effects of trihexyphenidyl chloride.

Background: Mimosa pudica Linn has been used in traditional medicine to support the treatment of type 2 diabetes. In the present study, we aimed to isolate and evaluate α-glucosidase and Protein Tyrosine Phosphatase 1B (PTP1B) inhibitory activities of bioactive compounds from Mimosa pudica’s leaf extract. Methods: Mimosa pudica leaves were extracted with 80% of ethanol. Bioactive compounds were isolated using a column chromatographic technique and elucidated the structure based on the nuclear magnetic resonance and electrospray ionization mass spectrometry spectral data. The α- glucosidase and PTP1B inhibitory activities of the isolated compounds were evaluated using pnitrophenyl phosphate and p-nitrophenyl-α-D-glucopyranoside as a substrate, respectively. Molecular docking and molecular dynamics are used to study the interaction between isolated compounds and proteins. Lipinski’s rule of five was used to evaluate the drug-like properties of isolated compounds. Predict pharmacokinetic parameters were evaluated using the pkCSM tool. Results: Protocatechuic acid and syringic acid were isolated and identified using spectroscopic methods. Protocatechuic acid and syringic acid considerably inhibited α-glucosidase enzyme at IC50 values of 416.17 ± 9.41 μM and 490.78 ± 9.28 μM, respectively. Furthermore, protocatechuic acid and syringic acid expressed strong PTP1B inhibitory activity at IC50 values of 248.83 ± 7.66 μM and 450.31 ± 7.77 μM, respectively. Molecular docking and molecular dynamics results showed the interactions of protocatechuic acid and syringic acid with amino acids of PTP1B and α-glucosidase enzyme. Lipinski’s rule of five and absorption, distribution, metabolism, excretion, and toxicity studies predicted that protocatechuic acid and syringic acid have drug-likeness properties. In molecular docking simulation, protocatechuic acid and syringic acid gave relatively negative free binding energies and interacted with many amino acids in the active sites of PTP1B and α-glucosidase. The molecular dynamics simulation results of the complexes were also relatively stable. Conclusion: Our results showed that protocatechuic and syringic acids could be promising compounds for type 2 diabetes treatment.

Background: α-Aminophosphonates are potentially biologically active species. Objective: We wished to compare the synthetic methods and evaluate the effect of the α- aminophosphonates on sarcoma cell lines. Methods: We investigated microwave-assisted Kabachnik–Fields and Pudovik reactions, as well as substitutions, and applied in vitro cytotoxicity screening. Results: The Kabachnik–Fields condensation and the Pudovik reaction were found to be the most suitable regarding efficiency. Surprisingly, the multidrug resistant (MDR) uterine sarcoma (Mes-Sa/Dx5) cell line was the most susceptible to the aminophosphonates tested. Conclusion: α-Aminophosphonates may indeed display anticancer effect. Substituents in the para position of the phenyl ring have an impact on the activity: the 4-Me and 4-Cl derivatives were more toxic to all cell lines as compared to the 4-H and 4-MeO species.