Letters in Drug Design & Discovery - Volume 21, Issue 7, 2024

Background: Lactucine is related to the sesquiterpene lactone group of naturally occurring compounds and has a variety of pharmacological effects including anticancer properties found in Chicory, Wormwood, Laurus nobilis, Pyrethrum, Chamomile, etc. Lactucine has an anticancer effect which may induce apoptosis in cancerous cells and protect other cells from getting infected. Objective: In this study, Lactucine and its derivatives were screened, and performed their in silico docking study with the proteins involved in the apoptosis-inducing effect in human leukemia cancer. Methods: The three-dimensional structure of lactucine and its derivatives were retrieved in the SDF format. Active sites of protein structures were determined by Sitemap. LigPrep module was used for geometrical refining of chemical structures of lactucine and its derivatives. The protein preparation wizard of Maestro (Schrodinger) was used for protein preparation. From the receptor-complex structure, the cocrystallized ligands were removed from the active site position of the receptor chain. All ligands were docked using default Glide settings for a grid centered on the ligand and structure. Flexible docking was performed using the extra precision (XP) feature of Glide module. The best docking poses for the lactucine and their derivatives were selected based on their docking score. The ADMET properties of lactucine 15- oxalate have been predicted by admetSAR software. Results: Proteins and ligands three-dimensional structures were retrieved from PDB and Pubchem databases, respectively. All lactucine derivatives suitably docked on the apoptosis-inducing proteins with ample Glide scores Lactucin 15-oxalate interacts with proteins which are responsible for apoptosis with a maximum of six H-bonds. Other types of interactions are also involved, like Pi-cation, Pi-Pi stacking, salt bridges, and halogen bonds. Protein CDK-4 has shown the highest number of H-bond (LYS142 salt bridges), ALA16, VAL14, ASP99, LYS35, TYR17, and ASN145) with the Lactucin 15-oxalate. ADMET properties of lactucin 15-oxalate met with the criteria of being eligible to be a novel drug for the treatment of human leukemia cancer. The Dock score of both the Dasatinib drug and the lactucine-15-oxalate with the apoptosis-inducing protein stipulates that the selected ligand has equitable interaction with the target proteins. Conclusion: In this study, lactucine derivatives were docked with apoptosis-inducing proteins for the prediction of its anticancer effect. Lactucin15-oxalate has shown the highest binding affinity for the CDK-4 target and can be used as a lead compound for cancer treatment. Glide and Dock score for docking of lactucin 15-oxalate with CDK-4, well as the number of hydrogen bonding, is in agreement to use this ligand for study. These in silico results are valuable to proceed with the in vitro and in vivo studies related to the anti-cancer role of lactucin 15-oxalate.

Background: Purpurin is being used as a red dye for many decades. But recently, due to its pharmacological properties, purpurin and its derivatives have attracted a lot of researchers for the treatment of various ailments, such as cancer, Alzheimer’s disease, depression, etc. Objectives: The objective of this study is to provide an overview of its pharmacological properties, pharmacokinetic studies, synthesis, isolation, quality assurance, and patent studies. Methods: A systemic scoping review was undertaken. Three databases (Pubmed, Scopus, and Google Scholar) and patent websites were searched using relevant words (e.g., purpurin, purpurin derivatives, anticancer, toxicity, etc.). All outcomes for studies that met the inclusion criteria were included in the review. Extracted data were accumulated using tables, figures, and accompanying narrative descriptive summaries. The review was reported using the preferred reporting items for scoping review (PRISMAScR) guidelines. Sixty-eight studies and eighty-six patents met the inclusion criteria, mostly preclinical (in vitro, in vivo, and in silico) studies performed in rats, mice, dogs, and zebrafish, followed by one clinical trial study. Results: The potent antioxidant nature of purpurin is the main reason behind its vast pharmacological properties. It acts by decreasing mitochondrial stress and by acting on the endoplasmic reticulum. It also crosses the BBB barrier, has high GI absorption, and follows the Lipinski rule, which makes it a good drug for various neurodegenerative disorders. It inhibits various CYP-450, CYP 1A2, and CYP 3A4 enzymes, which are responsible for causing mutations. It gets photosensitized by UV light and causes ROSdependent apoptosis in cancer cells. Conclusion: This scoping review highlights purpurin and its derivatives as highly prized moieties in the treatment of various neurological conditions and cancer. The unique nature of purpurin is responsible for its pharmacological properties, which are due to the presence of hydroxyl and keto groups at specific positions. It gets photosensitized by UV and laser light and acts as an anticancer drug. But the lack of robust evaluation in clinical studies is another major concern. Purpurin can be seen in the prescription in the future, although a lot of work still needs to be done.

Background: Myocardial infarction (MI) is an ischemic heart disorder that causes apoptosis or necrosis of myocardial cells. Objective: The study aimed to evaluate the effect of P-EKKE on myocardial infarction and explore the associated mechanisms in MI rats. Methods: The MI in rats was established by ligating the left coronary artery of rats; the rats were divided into the MI group (without treatment) and the P-EKKE group (treated with P-EKKE). Normal rats were assigned to the NC group (without treatment) and the sham group (under LAD without ligation). Cardiac function was evaluated using echocardiography. The MI area was measured with TTC staining. Histological analysis was performed to evaluate inflammation (HE staining) and myocardial fibrosis (Masson and immunofluorescence staining). RT-PCR and Western blotting were used to determine Gli-1/SHH expression in myocardial tissues. Results: P-EKKE clearly improved the cardiac function of MI rats. The area of myocardial infarction in MI rats undergoing P-EKKE treatment (P-EKKE group) was found to be predominantly decreased compared to MI rats without treatment (p < 0.05). P-EKKE treatment clearly inhibited apoptosis and increased H3S10ph expression in the area of myocardial infarction of MI rats compared to MI rats without treatment (p < 0.05). P-EKKE treatment significantly alleviated inflammation and decreased myocardial fibrosis in the area of myocardial infarction in MI rats compared to MI rats without treatment (p < 0.05). P-EKKE significantly increased the expression of Gil-1 and SHH in myocardial infarction of MI rats compared to MI rats without treatment (p < 0.05). Conclusion: P-EKKE inhibited myocardial infarction and played an anti-inflammatory and myocardial protective role in MI rats. P-EKKE inhibited myocardial inflammation by activating the hedgehog signaling pathway and inhibited myocardial fibrosis by decreasing α-actin expression.

Background: The drugs categorized under BCS class II and IV are poorly water-soluble, which in turn affects their dissolution and bioavailability. To overcome these limitations, namely, poor solubility and bioavailability, several approaches have been tried so far, like, co-solvency, size reduction or micronization, complexation, adsorption on high surface area carriers, etc. Objective: The present article aims to explore the utilization of the liquisolid technique to improve the dissolution profile of curcumin and quercetin, used as a combination in a solid dosage form. It covers the study of the impact of various carriers employed in liquisolid technology on drug dissolution profiles; Avicel pH 101, Fujicalin and Neusilin were used as carriers in this study. Methods: The solubility of the drugs was evaluated in various non-volatile solvents except water to select the vehicle having maximum solubility. All formulations were then prepared using curcumin and quercetin in a ratio of 2:1 (150 mg curcumin : 75 mg Quercetin), comprising a proportion of 40-60% w/w of the total mass of the formulation and were estimated for post-compression parameters. During the final processing of the liquisolid compacts, the carrier is to coating material ratio was kept consistent, i.e., 20:1. Results: Powder X-ray Diffraction (PXRD) and Fourier Transform Infrared Spectroscopy (FTIR) were utilized to analyze drug-excipient interaction; these studies stated no evidence of any physical or chemical interaction between drug(s) and the excipients. The final product was then evaluated for the liquid adsorption capacity and in vitro release of the drugs as a combination, and it was observed that these two properties were found to be significantly improved in the liquisolid compacts. Conclusion: The outcomes indicated that the combination of Neusilin as the carrier and castor oil as a non-volatile solvent was the best-performing formulation appropriate for targeting an improved dissolution profile.

Background: The frightening rise of bacterial resistance is occurring worldwide and endangering the efficacy of antibiotics. Hence, the development of novel and potent antibacterial is a need of the day. Objective: In this study, we designed and synthesized compounds C1-C11. These compounds are characterized by their FT-IR, NMR and MS spectral data and examined in vitro for their antibacterial activity. Methods: Compounds C1-C11 were synthesized by reacting 2-mercaptobenzothiazole with appropriate chloroacetamide in the presence of anhydrous potassium carbonate and dry acetone at room temperature. To assess the antibacterial activity, minimum inhibitory and minimum bactericidal concentrations were examined by broth microdilution method against the selected strains of both Gram-positive and Gramnegative bacteria. Time-kill kinetics study was also performed as per CLSI guidelines. Results: Compounds C6 and C7 displayed promising activity against Staphylococcus aureus ATCC 43300 with MICs of 9.43 and 7.73 μM, respectively. These two compounds also displayed promising antibacterial activity against S. aureus 5021 with MIC values of 7.53 and 9.68 μM, respectively. In MBC determination, these two compounds (tested in the concentration range of 7.53 to 262.3 μM) displayed bactericidal activity against methicillin resistant S. aureus ATCC 43300, S. aureus NCIM 5021 and S. aureus NCIM 5022. In time-kill kinetics study, compounds C6 and C7 also exhibited bactericidal activity against S. aureus NCIM 5021 and S. aureus ATCC 43300 after 12 h of exposure. In general, all tested compounds exhibited poor activity against Mycobacterium sp. NCIM 2984 and also against tested Gramnegative bacteria Klebsiella pneumoniae NCIM 2706, Escherichia coli NCIM 2065 and Pseudomonas aeruginosa NCIM 2036. Further, computed ADMET properties of C1-C11 showed a favourable pharmacokinetic profile with zero violation of Lipinski's rule of five. Conclusion: The result showed that in phenylacetamides C6 and C7 presence of phenyl ring substituted with -CF3 group is responsible for their high antibacterial activity against S. aureus ATCC 43300 (MICs, 9.43 and 7.73 μM, respectively). These two compounds also exhibited bactericidal activity respectively against S. aureus NCIM 5021 in time kill kinetics study.

Background: 2-pyridone is frequently used to synthesize and develop new bioactive molecules approved for treating many diseases. The produced compounds play a significant role in inhibiting cancer growth. Objective: Through a molecular docking investigation, we determined the binding affinity of 2-pyridone compounds with the Matrix Metalloproteinase receptor, which allowed us to develop, produce, and test the in vitro anticancer efficacy of those compounds. Methods: 2-pyridones (A1-A12) were synthesized in a multistep process, followed by spectrum analysis to confirm the structure. In silico screening of the synthesized compounds was carried out with the assistance of AutoDock software. Flow cytometry was used on the HT-29 colon cancer cell line to measure A1-A12’s anticancer effect in a lab setting. Results: The enzyme matrix metalloproteinase receptor and A1-A12 interacted unexpectedly during a docking study (MMP3, MMP9 & MMP13). Research has shown a strong affinity for MMP3 receptors for A9, A10, A11, A12, and A4, respectively. Further flow cytometric testing revealed compound A9 (R1) to be highly cytotoxic, with an IC50 value of 20.77 M. The anticancer activity of A9 (R1) against HT-29 colon cancer cell lines was also confirmed by in vitro results. Conclusion: These findings suggested that 2-pyridone compounds have promising therapeutic potential for cancer treatment, and more research on these lead moieties would be advantageous to discovering an effective anticancer drug.

Background: Fragrances are the collection of unlike functional assemblies, most likely alcohols, esters, aldehydes, ketones, and acids in organic products/hydrocarbons. Short-chain aliphatic fragrance esters have immense applications as flavors in the food, pharmaceutical and cosmetic industries and also have remarkable commercial significance in cosmetics and personal care products like perfumes, face creams, shampoos, soaps, lotions, jams, jellies, etc. Objective: This study aimed to synthesize short-chain fragrance esters using a whole-cell lipase catalyst from Aspergillus flavus (RBD-01). Methods: The present study emphasizes the synthesis of artificial flavoring compounds by using a wholecell biocatalytic process, which can have wide significance. Herein, the preparation of ethyl alkanoates (ethyl propanoate to ethyl decanoate) was performed to investigate the flavors and fragrance excellence. The biomass from Aspergillus flavus (RBD-01) was used as a catalyst to facilitate the remarkable esterification activities towards the synthesis of important aroma esters with the help of a series of short-chain acids and alcohols. Results: The ethyl hexanoate (4) among all synthesized alkanoates was found to have a fruity fragrance with a good conversion rate. Further synthesized alkyl hexanoates (4A-4I) were found to have good fruity/pineapple/berry flavors and significant aroma quality. Conclusion: These results implied that whole-cell lipase of Aspergillus flavus (RBD-01) is a promising biocatalyst in the production of flavor aroma esters and can boost production in the food/cosmetic manufacturing industries.

Background: SARS-COVID-19 is an infectious disease, the causative agent Caroni virus. WHO announced the pandemic on 3rd November 2020 to the whole world. Objective: Severe Acute Respiratory Syndrome COVID-19 is an infectious disease globally declared a pandemic by WHO. There is a need to find the proper medication for recovery. The study uses the molecular docking method to predict the anti-covid activity of plant phytoconstituents of Tamarind indica. Methods: Molecular docking techniques were accomplished to search the binding pattern of plant phytoconstituents of T. indica against the crystal structure SARS-CoV-2 enzyme (PDB ID: 6LU7) with the help of PyRx virtual screening software to study the amino acid interaction and inhibitory potential of phytoconstituents of T. indica. In addition, we performed a pharmacokinetic and toxicological study of plant phytoconstituents of T. indica using SwissADME and the pkCSM online server. Results: The phytoconstituents of Plant T. indica docking results proposed that apigenin (-7.8 kcal/mol), epicatechin (-7.1 kcal/mol) and taxifolin (-7.5 kcal/mol) show the best binding energy as compared to favipiravir (-5.2 kcal/mol). The phytoconstituents exposed promising interaction with amino acid residue, leading to an inhibitory effect against the SARS-CoV-2 enzyme (PDB ID: 6LU7). Further, ADMET studies showed that pharmacokinetics and toxicological parameters are within acceptable limits. Conclusion: In silico study revealed that the phytochemicals of T.indica show promising inhibitory results against the SARS-CoV-2 enzyme (PDB ID: 6LU7). Moreover, the traditional benefits of T.indica were clinical treatment and drug discovery.

Background: Cancer is a condition that involves the irregular progression of cells with the capacity to enter and move to other portions of the body. Peto’s paradox shows there is no relation between large body size and cancer risk. Objective: To assess the phylogenetic analysis of oncogenes and tumor suppressor genes of breast cancer. Methods: Data was collected from the ensemble genome browser and NCBI. A BLAST search was done, and FASTA sequences were collected. MEGA X version 5 software was used for phylogenetic analysis. Alignment was made by Clustal W, and two trees were constructed as a neighbor-joining tree and maximum likelihood trees as vertical and circular. The accuracy was confirmed by the bootstrap method (at 500 pseudoreplicates). Results: The results show that there were 9 copies of the tp53 gene in elephants are present due to which elephants have less chance of getting cancer. This proves that Peto’s paradox is true. The evolutionary study of genes set, present on the FGFR-bearing chromosomes, i.e., Hsa1 to Hsa4, Hsa6 to Has 9, Hsa11 to Hsa14, Hsa17, Hsa18, Hsa21, Hsa22, and HsaX. The phylogenetic trees of 10 gene families, including 4 genes from tumor suppressor genes and 6 genes from oncogenes, were generated with vertebrate sequences. Conclusion: Higher animals have less chance to develop cancer because of huge body mass and longevity and increased number of genes in their body. Different oncogenes and tumor suppressor genes are associated with different species. All genes have two or more paralogues except BRCA, CHECK, MEN, NUP, and SUFU genes.

Background: The epidermal growth factor receptor (EGFR) is a member of the tyrosine kinase receptor family known as ErbB. The EGFR signaling pathway is an important regulator of cell proliferation, differentiation, division, and survival, as well as cancer development in humans. Epidermal growth factor, betacellulin, amphiregulin, transforming growth factor and heparin-binding EGF-like growth factor are high-affinity ligands of EGFR. Objective: Tumor progression can be effectively prevented by inhibiting EGF/EGFR interactions. In this study, many anti-EGF peptides targeting EGFR binding regions were designed, modeled, and evaluated. After selecting the peptides with the highest binding energy to the EGF, the interactions between the candidate peptides and all of the key EGFR ligands were investigated. Methods: To identify an EGF-binding peptide capable of blocking EGFR-EGF interactions, large-scale peptide mutation screening was performed. Using the AntiCP server, several possible peptides with anticancer properties were identified. The ClusPro analysis was performed in order to analyze the interactions between EGF and all of the library peptides. A total of five peptides with favorable docking scores were identified. The stability of three peptides with the best docking scores in complex with EGF was verified, applying molecular dynamics simulation with the help of the GROMACS software package. Finally, the interaction of candidate peptides with transforming growth factor-alpha, heparin-binding EGF-like growth factor, and betacellulin was investigated using the ClusPro server. Results: After the screening of modeled peptides by the ClusPro server and GROMACS software, two anti-EGF peptides of Pep4 and Pep5 with 31 residues were developed. Then, we demonstrate that both of these peptides can bind to the other high-affinity ligands of EGFR and block TGFA/EGFR, HBEGF/EGFR, and BTC/EGFR interactions. Conclusion: The findings suggest novel insights for developing therapies based on peptides for inhibiting the EGF, TGFA, HBEGF, and BTC signaling cascade in cancer cells. Pep4 and Pep5 designed in this work, are recommended as potentially promising anticancer peptides for further experimental evaluation.

Background: Alzheimer’s disease (AD), a chronic neurodegenerative disorder predominantly occurs among the elderly, is the leading cause of dementia. The accumulation of β-amyloid (Aβ) is considered the main pathogenies of AD, and β-site APP-cleaving enzyme 1 (BACE1) plays an important role in the formulation of Aβ. Objective: In order to find a new scaffold as BACE1 inhibitors, a series of novel 2-amino-1-phenylbenzimidazole derivatives were designed and synthesized in this work. Methods: Using our previous L-5 as a lead compound, we applied a scaffold hopping method and merged 2-amino-1-methyl-4-phenyl-1H-imidazol-5 (4H)-one into benzimidazole, so a novel class of BACE1 inhibitors T1~T20 with the structure of 2-amino-1-phenyl-benzimidazole were designed and synthesized. Results: The biological activity evaluation indicated that the target compounds showed inhibitory activities against BACE1, with T14 being the most potent (IC50 = 0.45 μM), it also exhibited good logP value and tPSA. The docking studies indicated that compound T14 could form important hydrogen bonds with Asp289 and Asp93. Conclusion: Compound T14 could be used as a potential BACE1 inhibitor for further modification to treat AD.

Background: As one of the main by-products of mango production, the mango peel is rich in multiple polyphenols, such as mangiferin. Therefore, there is an urgent need to explore the potential mechanism of mangiferin for nutrition intervention of oxidative stress-related diseases. Methods: Mangiferin was extracted and purified from the mango peel and was identified by the reverse phase high-performance liquid chromatography. The antioxidant potential of mangiferin was determined in vitro (potassium ferricyanide reducing capacity, DPPH, hydroxyl radicals scavenging ability, and superoxide anion radicals reducing capacity). In order to explore the potential mechanism for the antioxidant activity of mangiferin, a combination of network pharmacology and molecular docking approaches was performed. Results: The purity of mangiferin from the mango peel was ≥ 95.0%, and its antioxidant activity was confirmed by different in vitro assays. ALB, ESR1, CASP8, CASP3, BCL2L1, CXCL8, AKT1, CTNNB, and EGFR were identified as the potential oxidative stress-related targets of mangiferin. These results suggested that mangiferin might play a key role in the antioxidant process through multi-targets. Conclusion: Integrated with network pharmacology and molecular docking methods, this work demonstrated the potential mechanism of mangiferin for nutrition intervention of oxidative stress-related diseases.

Background: Due to the complication caused by conventional drugs, global attention has been focused on the development of novel drugs. As a consequence, a potential theory to put T2DM under control is of great medical significance. Methods: We used the heuristic method to establish the linear model and used Gradient Boosting Regression to establish the nonlinear model of Fructose-1,6-Bisphosphatse inhibitor successively. In this study, 84 derivatives of N-Arylsulfonyl-Indole-2-Carboxamide were introduced into the models, and two outstanding QSAR models with 2 molecule descriptors were established successfully. Results: Gradient Boosting Regression rendered a good correlation with R² of 0.943 and MSE of 0.135 for the training set, 0.916 and 0.213 for the test set, which also proves the feasibility of the implementation of the new method GBR in the field of QSAR. Meanwhile, the optimal model displayed wonderful statistical significance. Conclusion: This study makes an attempt at the application of a new method of GBR in QSAR and proves GBR as a promising tool for further study of CADD.