Letters in Drug Design & Discovery - Volume 20, Issue 5, 2023

Lung cancer is a leading cause of cancer-related deaths globally. The availability of successful anticancer agents in the market is limited, and the development process of a new drug molecule is slow and difficult. The currently available commercial formulations are not sufficient to produce the desired therapeutic response within a specific time limit. Therefore, there is an urgent need to develop novel nanocarrier-based therapies to defeat the restrictions of existing therapeutics. Nanoparticles have been investigated as novel formulations but are often inefficient in practical applications. However, several unanswered questions and challenges exist in their clinical development; thus, a better understanding of their influence on cancer biology, stability, and toxicity needs to be gained. This review discusses different types of lung cancers as well as diagnostic approaches to lung cancer. The review also explores the drug targeting mechanisms to cancer cells through nanoparticles and multi-drug resistance-associated challenges in lung cancer therapy. Various nanocarrier systems that are safe and effective for drug delivery in the treatment of lung cancer have been discussed. This communication will be of high relevance to the biological, formulation, and translational scientists working in the field of cancer biology and drug delivery.

Background: Feronia elephantum (Rutaceae), frequently named wood apple, is a preferable medicinal plant. In Ayurveda, its bark has been recommended for treating diabetes. In addition, it is one of the active chemical constituents, decursin, shown in recent research to significantly impact colon cancer, breast cancer, Alzheimer's disease, inflammation, and ulcerative colitis. Objective: The present study was carried out to investigate the traditional use of Feronia elephantum bark in streptozotocin-induced diabetes and lipid-lowering action in rats. Decursin has been isolated from the bark and tested for in vitro and in vivo biological activities. Methods: The Soxhlet extraction method obtained the ethanolic extract, and fractionation was done with column chromatography and TLC. The structure of isolated decursin has been confirmed by Fourier transform infrared (FTIR) and nuclear magnetic resonance (NMR) spectroscopy. Results: The decursin noticeably depletes increased blood glucose levels and positively affects altered lipid profiles after administering a dose of 150 mg/kg orally compared with the hypoglycemic drug metformin. In molecular docking simulations, decursin exhibited excellent inhibition of α-amylase, dipeptidyl peptidase-IV, and moderate activity against α-glucosidase and glucokinase. Furthermore, the enzymes 3- hydroxy-3-methylglutaryl coenzyme A and Niemann-Pick C1-Like 1 are ideal targets to control hyperlipidemia and have shown moderate inhibition by decursin. Conclusion: From these results, it has been concluded that decursin is the perfect candidate for further optimization as a lead molecule to treat diabetes and hyperlipidemia.

Background: The insulin receptor protein of humans is proposed to have substantial application in the regulatory pathway of glucose levels in the blood. The cellular function of the insulin hormone is initiated by its association with the insulin receptor (IR) protein, and this process is common to most vertebrate species. Thus, phylogenetic analysis of IR protein among various associated species in vertebrates can elucidate the importance of residues and structure, and the relationship with its function as the conserved region of residues is associated with evolutionary conservation on insulin receptor proteins. In the present study, we have used various in silico approaches and conducted the phylogenetic analysis. Methods: The basic local alignment search tool (BLAST) was employed to screen the 250 vertebrates. After evolutionary analysis, Pan troglodytes (Chimpanzees) have been observed as the closest relatives of Homo sapiens concerning insulin receptor proteins. Results: Human insulin receptor protein was found to have hydrophobic nature by hydrophobicity profile analysis, where most of the positions were above the mean hydrophobicity value from n-terminal to cterminal residues, whereas carboxy-terminal residues were observed as hydrophilic. High entropy was observed at the short stretch at N-terminal, C-terminal, and a linker region within the alignment, but the overall positions which were aligned showed low entropic regions. Conclusion: The outcomes of this work have revealed some unexplored specific characteristics of the conserved domains among different taxa of selected vertebrates and have also illustrated the hierarchical assemblage-based inconsistent variation of the IR proteins, and further conservancy analysis discloses the significance of each site for protein structure or function.

Introduction: In this work, we used several molecular modeling techniques to design new molecules for the treatment of non-small cell lung cancer (NSCLC). Methods: For this purpose, we applied 3D-QSAR, molecular docking, MOLCAD, ADMET, and MMGBSA studies to a series of 51 natural derivatives of magnolol. Results: The developed models showed excellent statistical results (R² = 0.90; Q² = 0.672; R²pred = 0.86) for CoMFA and (R² = 0.82; Q² = 0.58; R² pred = 0.78) CoMSIA. The design of eleven new molecules was based on predictions derived from the 3D-QSAR model contour maps, molecular docking and MolCAD analyses. In silico drug-like and ADMET properties studies led to the selection of four new molecules designed as potential agents for NSCLC therapy. Molecular docking and MM-GBSA simulations of proposed structures with EGFR-TKD (PDB code: 1M17) showed that ligands X10 and 30 attained better stability in the 1M17 protein pocket compared to the Erlotinib ligand used as a reference. Conclusion: Incorporating all the molecular modelling techniques used in this work is conducive to the design of new molecules derived from the 3-(4-aminobipyridin-1-yl)methyl structure of magnolol, a candidate for drug design for the treatment of non-small cell lung cancer. Therefore, the molecular structures (X10 and 30) can be proposed as a key to designing new drugs against NSCLC.

Background: Tuberculosis is a worldwide health concern, and there is an immediate need for effective therapeutics to inhibit the infection caused by Mycobacterium tuberculosis. The persistent state of bacteria and the emergence of Multi-Drug Resistance are the two major reasons for the difficulty in treating tuberculosis. Objective: The study aims to identify novel phytocompounds to effectively inhibit Mycobacterium tuberculosis by targeting the Esx-1 protein, which plays a vital function in the secretion pathway of M. tuberculosis to successfully disrupt the host cell and cause tuberculosis. Methods: In the current study, ~500 novel phytocompounds were screened by docking against Esx-1 using AutoDock Vina 4.2 version. The visualization analysis for selected phytocompounds was performed using Protein-Ligand Interaction Profiler. A comparative study with a well-known drug for tuberculosis, Rifampicin, was also performed. Moreover, ADMET analysis was performed to check the druggability and pharmacokinetic parameters of the selected compounds. Results: Based on the analysis, cadabicine, an alkaloid produced by Cadaba fruticose (Vizhuthi), Crataeva nurvala (Varuna) plants, exhibits the best binding affinity of -7.8 Kcal/mol with the active site residues, Leu 29 and Trp 43, of Esx-1, which are required for the stability of Esx-1 and virulence of M. tuberculosis in the host cell. ADMET analysis showed that cadabicine exhibits better druggability and pharmacokinetic parameters than other selected compounds. Conclusion: Cadabicine possesses an acceptable binding affinity with the active site of Esx-1 and exhibits acceptable physicochemical and pharmacokinetic properties, which makes it a potential new drug candidate for the treatment of tuberculosis.

Background: Indazole is a promising structure present in various biological activity compounds; in particular, many 6-aminoindazole-containing compounds demonstrated anticancer activity. In our previous research, we discovered some of the 6-aminoindazole derivatives with excellent cytotoxicity in the human colorectal cancer cell line (HCT116). Objective: In this study, a series of 6-substituted amino-1H-indazole derivatives were designed and synthesized through simple and well-known chemical reactions, which were evaluated for anti-proliferative activity in four human cancer cell lines. Methods: The title compounds were designed based on the structures of potential anticancer candidates in our previous report. The synthesis of 6-aminoindazole derivatives through acetylation and reductive amination with 6-amininoindazole as the starting material. Sulforhodamin B (SRB) assay was used for in vitro biological evaluation of synthesized compounds. Various physicochemical properties of them were predicted by online site Molinspiration. Results: Seven out of eight synthesized compounds showed growth inhibitory activity with IC50 values from 2.9 to 59.0 μM range in all four tested cancer cell lines. Of them, the compound N-(4-fluorobenzyl)- 1H-indazol-6-amine (9f) exhibited a potent anti-proliferative activity, with an IC50 value of 14.3±4.4 μM in the human colorectal cancer cell (HCT116) and non-cytotoxicity in the normal cell (lung fibroblast cells, MRC5, IC50 >100 μM). Conclusion: The bioactivity result and conformance of the physicochemical properties of the synthesized compounds to the "rule of three" for hit-like compounds suggested that 9f was effective and could be used as a hit for the development of novel anticancer agents.

Background: Recently, the essential oil (EO) of Ammodaucus leucotrichus has attracted particular attention in hemi-synthesis due to the reactivity of its main monoterpenes. Objective: In vitro cytotoxic and antileishmanial activities of the EO and hemi-synthesized compounds were evaluated, and an in-silico simulation was conducted. Methods: The EO was characterized by GC-MS. Two benzodiazepines (C1, C2), benzimidazole (C3), and Schiff base (C4) were hemi-synthesized by an in situ condensation of its major monoterpenes (perillaldehyde) with different amine derivatives. Synthesized compounds and the EO were evaluated for their cytotoxic activity against laryngeal carcinoma-Hep2 and rhabdomyosarcoma-RD cell lines and for their antileishmanial activity against Leishmania (L) major. Molecular docking was performed to pin the binding interactions of active molecules. Results: A significant cytotoxic effect of benzodiazepines C1 and C2 was noted against Hep2 cells (IC50/C1 = 39.48 ±0.7 μM, IC50/C2 = 48.82±1.33 μM) and RD (IC50/C1 = 15.96±1.99 μM; IC50/C2 = 74.3±2.44 μM), while the EO highly inhibited Hep2 cell lines (IC50/EO = 17.3±0.85 μg/mL). C4 strongly inhibited L. major growth with an IC50 value of 8.00±1.37 μ. The docking scores of ligand-C4 on L. major pteridine reductase and L. major methionyl-tRNA synthetase and ligands-(C1, C2) on the human protein kinase and epidermal growth factor kinase presented significant affinity to the receptor active sites (ΔG from -7.7 to -8.8 kcal/mol). Conclusion: The cytotoxic effect of derivatives C1, C2, and EO, as well as the anti-parasitic effect of C4, may suggest them as effective bioactive agents or pharmaceutical probes.

Introduction: Nipah virus (NiV) is a highly pathogenic zoonotic virus of the genus Henipavirus, which causes severe respiratory illness and deadly encephalitis with a fatality rate of 50%- 70 % in humans. A total of 16 NiV proteins are available in the Protein Data Bank (PDB) of which six proteins belong to the structural class. Methods: In this study, a cluster of six proteins of classes Viral attachment glycoproteins (2VWD, 2VSM), Fusion glycoprotein (5EVM, 6PD4), Matrix protein (6BK6), and Phosphoprotein (4HEO) were considered as potential therapeutic targets. Here, 25 small molecule inhibitors were chosen, which include 23 natural compounds with antiviral properties and 2 antiviral drug molecules as control. The potential inhibitors among the selected compounds were identified based on docking score, significant intermolecular interactions, ADME (absorption, distribution, metabolism, and excretion) properties, pharmacophore and toxicity studies. Moreover, 100 nanoseconds molecular dynamics simulation was carried out for the best selected compound with all protein targets to understand the stability and binding strength. Results and Discussion: In this study, we propose that the baicalin was found to be the most potential lead molecule with higher binding affinity, strong bonded interactions, favorable pharmacophore features and higher complex stability. Conclusion: Hence, the compound identified shall prove effective against the Nipah virus by targeting the viral attachment glycoprotein.