Deciphering the anticancer potential of Lannea coromandelica targeting apoptosis signal-regulatory kinase 1 via advanced computational biology approaches

Breast cancer (BC) remains a leading cause of cancer-related mortality in women. The oncoprotein MDM2 negatively regulates the tumor suppressor p53, and its overexpression in BC promotes tumor progression and resistance to therapy. Targeting the MDM2-p53 interaction represents a promising therapeutic approach. However, many existing MDM2 inhibitors suffer from poor pharmacokinetics and off-target toxicity, necessitating the discovery of novel, more selective alternatives. This study aims to identify natural terpenoid compounds with potent MDM2 inhibitory potential through computational approaches. A library of 398 natural terpenoids was sourced from the NPACT database and filtered based on Lipinski's Rule of Five. A two-stage docking strategy was applied: 1) rigid protein-flexible ligand docking to screen for high-affinity binders, followed by 2) ensemble docking using multiple MDM2 conformations derived from molecular dynamics (MD) simulations. The top candidates were further evaluated for their pharmacokinetic and toxicity profiles using ADMET analysis. Finally, 150ns MD simulations and binding free energy (MM-PBSA) calculations were performed to assess the stability and strength of protein-ligand interactions. Three terpenoid compounds, olean-12-en-3-beta-ol, cabralealactone, and 27-deoxyactein demonstrated strong binding affinities toward MDM2 in ensemble docking studies. ADMET analysis confirmed their favorable pharmacokinetic properties. Further MD simulations indicated that these compounds formed highly stable complexes with MDM2. Notably, 27-deoxyactein exhibited the lowest binding free energy (-154.514kJ/mol), outperforming the reference inhibitor Nutlin-3a (-133.531kJ/mol), suggesting superior binding stability and interaction strength. Our findings highlight 27-deoxyactein as a promising MDM2 inhibitor with strong binding affinity, stability, and a favorable pharmacokinetic profile. This study provides a computational foundation for further experimental validation, supporting the potential of terpenoid-based MDM2 inhibitors in BC therapy.

TRK fusion proteins, encoded by gene fusions in NTRK family of genes are responsible for different types of cancers. Resistance and adverse effects of available TRK inhibitors viz., larotrectinib and entrectinib necessitate the search for safer alternatives. This study was aimed to identify novel TRK inhibitors from a series of pyrazolo‐pyridine derivatives based on advanced computational approaches. 3D‐QSAR modelling, Virtual screening, ADMET analysis and Molecular Docking helped to identify novel TRK inhibitors. Results were validated based on MM‐GBSA, MD simulations and DFT analysis. The 3D‐QSAR modeling showed strong predictability (R2 = 0.9080; Q2 = 0.672), resulted in identification of compound E7, while compound DB4093 emerged as a top candidate from virtual screening. Favourable pharmacokinetic profile was indicated by ADMET studies. Both compounds, E7 and DB4093 have demonstrated strong binding affinity viz., −10.39 Kcal/mol and −12.05 Kcal/mol respectively with the TRK receptor, forming multiple stable hydrogen bonds with key active site residues. MM‐GBSA analysis has shown favourable binding free energies as compared to (Entrectinib −32.419 kcal/mol). Stable bindings were confirmed by MD simulations and DFT analysis. Our research work has led to the identification of E7 and DB4093 as promising TRK inhibitors warranting further experimental validation.

Non-small cell lung cancer (NSCLC) accounts for 85-90% of global lung cancer cases and causes over 1.7 million deaths annually worldwide. Despite therapeutic advancements, existing treatments remain expensive and are often associated with significant side effects, underscoring the need for alternative drug candidates. Natural compounds offer promising prospects as safer and more affordable therapeutic options for NSCLC. Toxicodendron succedaneum, a medicinally important plant species from the family Anacardiaceae, contains a diverse phytoconstituents with potential anticancer activity. Investigating these bioactive compounds may uncover therapeutic potential to facilitate NSCLC drug discovery. In this study, a comprehensive structure-based drug design approach was employed to identify drug candidates targeting the extracellular signal-regulated kinase 2 (ERK2) receptor. Using molecular docking, molecular dynamics (MD) simulation, ADMET analysis, MM/GBSA calculations, and DFT assessments, two lead compounds: rhusflavone ( - 10.9kcal/mol) and hinokiflavone ( - 9.9kcal/mol), were identified, both revealing favorable drug-likeness and toxicity profiles. MD simulation spanning 500ns timescale confirmed the structural stability of the identified leads, further corroborated by principal component analysis (PCA) and Gibbs free energy landscape (FEL) evaluations. Rhusflavone emerged as the most promising candidate, with a free binding energy of - 57.15 ± 5.28kcal/mol. DFT analysis revealed enhanced molecular reactivity of the lead compounds upon transitioning from the free to the bound states. These results could contributeto the development of novel lung anticancer drugs, warranting further in vitro and in vivo validation.

Inflammation is caused by a cascade of events, one of which is the metabolism of arachidonic acid, that begins with oxidation by the enzyme 5-lipoxygenase. 5-Lipoxygenase (5-LOX) plays an important role in the inflammation process by synthesizing leukotrienes and several lipid mediators and has emerged as a possible therapeutic target for treatment of inflammatory diseases such as asthma and rheumatoid arthritis. Most of the existing 5-LOX inhibitors are synthetic and exhibit adverse side effects. In view of this, there is need to search for an alternate source of 5-LOX inhibitor with minimal side effects. The essential oil of several species of Curcuma has received considerable attention in recent times in traditional system of medicine especially for treating various inflammatory disorders. Therefore, the present study was carried out to screen the most potential 5-LOX inhibitors from essential oil components of Curcuma species and elucidate their mechanisms of action through computational biology approaches. Twenty-three phytoconstituents derived from the essential oil of Curcuma species were docked and their predictive binding energies were calculated to select the best possible ligand for 5-LOX. The top 8 ranked compounds from docking was tested for drug-likeness properties, bioactivity score, and toxicity analysis. The phytoconstituents such as α-turmerone, β-turmerone, α-terpineol and dihydrocarveolshowed the best binding affinity with 5-LOX and displayed favorable physicochemical properties. Molecular dynamics simulation in POPC lipid bilayers was carried out to understand the intrinsic dynamics and flexibility of the 5-LOX (apo) and 5-LOX-complex (α-terpineol, α-turmerone, β-turmerone and dihydrocarveol) systems. The molecular dynamic results showed that these 4 phytoconstituents interacted stably with the 5-LOX active site residues and the important bonds that were observed in the initial ligand docked compounds did not alter during the course of simulation. In general, our integrative computational approach demonstrated that the natural compounds like α-turmerone, β-turmerone, α-terpineol, and dihydrocarveol could be considered for designing specific anti-inflammatory drugs using structure-based drug design.

The present study explores the angiosperm flora belonging to the class Liliopsida in Rajbari district, seamlessly integrating taxonomy with phytocompound-based drug discovery through advanced computational biology approaches. The study covered all five upazilas (sub-districts) of the district. A total of 201 taxa across 118 genera and 24 families of Liliopsida were identified. The flora is predominantly composed of herbs (79.06%), followed by climbers (7.96%), trees (7.46%), shrubs (2.98%), and a minimal occurrence of epiphytes (1.99%). Poaceae emerged as the largest family, comprising 58 taxa across 36 genera, followed by Araceae (26 taxa) and Cyperaceae (17 taxa). Notably, the study identified 25 medicinal plant species under Liliopsida. Some rare species within Liliopsida, such as Coix aquatica, Wolffia arrhiza, Typha domingensis, and Schumannianthus benthamianus were also recorded in the study area. Among the medicinal plants identified, Amorphophallus paeoniifolius (Dennst.) Nicolson was selected for further investigation into colorectal cancer drug discovery. The computational therapeutics design endeavor unveiled two lead compounds: Riboflavin (-7.9 kcal/mol) and Lupeol (-6.1 kcal/mol), both of which demonstrated promising favorable drug-likeness properties. Molecular dynamics simulation spanning 100 ns revealed structural stability of the identified leads. PCA and Gibbs free energy landscape study further corroborated the drug-candidacy of the leads. DFT-based molecular reactivity study unveiled Lupeol as the most kinetically stable compound (6.915 eV). The findings highlight the significance of multi-disciplinary approach integrating classical taxonomy with bioinformatics and pave the way for future colorectal cancer therapeutics. Bangladesh J. Plant Taxon. 31(2): 239-264, 2024 (December)

Peramivir, a potent influenza neuraminidase inhibitor, serves as a basis for designing similar inhibitors targeting viral, mammalian, or bacterial neuraminidases. This study employs molecular modeling, including docking, ADMET analysis, and topological approaches (ELF, RDG, AIM), to investigate the structural features essential for influenza A virus inhibition, focusing on hydrogen bonding interactions. Compounds 7 and 8 were evaluated for their potential to target oseltamivir-resistant influenza A virus binding sites. Binding affinity was assessed using AutoDock Vina, and 100 ns molecular dynamics (MD) simulations confirmed their stability. Free binding energy calculations showed that these compounds exhibit higher stability than the standard drug. The findings provide insights into the structure–activity relationship of substituted peramivir phosphonates, supporting their potential as lead compounds for early-stage drug development against influenza A infections.

Oxidative stress (OS), generated by the overrun of reactive species of oxygen and nitrogen (RONS), is the key cause of several human diseases. With inflammation, OS is responsible for the onset and development of clinical signs and the pathological hallmarks of Alzheimer's disease (AD). AD is a multifactorial chronic neurodegenerative syndrome indicated by a form of progressive dementia associated with aging. While one-target drugs only soften its symptoms while generating drug resistance, multi-target polyphenols from fruits and vegetables, such as ellagitannins (ETs), ellagic acid (EA), and urolithins (UROs), having potent antioxidant and radical scavenging effects capable of counteracting OS, could be new green options to treat human degenerative diseases, thus representing hopeful alternatives and/or adjuvants to one-target drugs to ameliorate AD. Unfortunately, in vivo ETs are not absorbed, while providing mainly ellagic acid (EA), which, due to its trivial water-solubility and first-pass effect, metabolizes in the intestine to yield UROs, or irreversible binding to cellular DNA and proteins, which have very low bioavailability, thus failing as a therapeutic in vivo. Currently, only UROs have confirmed the beneficial effect demonstrated in vitro by reaching tissues to the extent necessary for therapeutic outcomes. Unfortunately, upon the administration of food rich in ETs or ETs and EA, URO formation is affected by extreme interindividual variability that renders them unreliable as novel clinically usable drugs. Significant attention has therefore been paid specifically to multitarget EA, which is incessantly investigated as such or nanotechnologically manipulated to be a potential "lead compound" with protective action toward AD. An overview of the multi-factorial and multi-target aspects that characterize AD and polyphenol activity, respectively, as well as the traditional and/or innovative clinical treatments available to treat AD, constitutes the opening of this work. Upon focus on the pathophysiology of OS and on EA's chemical features and mechanisms leading to its antioxidant activity, an all-around updated analysis of the current EA-rich foods and EA involvement in the field of AD is provided. The possible clinical usage of EA to treat AD is discussed, reporting results of its applications in vitro, in vivo, and during clinical trials. A critical view of the need for more extensive use of the most rapid diagnostic methods to detect AD from its early symptoms is also included in this work.

Introduction: An emerging impetus has driven the development of various smallmolecule compounds for the management of type 2 diabetes. With the advent of novel heterocyclic derivatives, an expansive field of pharmacological endeavors has opened up to stimulate Glucokinase (GK) activation. Recent evidence has validated GK';s legitimacy as a potential target for pharmaceutical intervention in diabetes. Glucokinase, an enzyme critical to maintaining blood glucose equilibrium, malfunctions in individuals with type 2 diabetes. A key component of this innovative approach is the use of heterocyclic derivatives to stimulate the GK enzyme, thereby serving as powerful pharmaceutical agents to improve type 2 diabetes management substantially. Methods: Maybridge';s digital archive contained 53,000 compounds, known for their efficacy, which were subjected to thorough examination. From this extensive repository, 422 compounds with an indole core were identified. The structures generated by ChemBioDraw Ultra through this method were meticulously docked using AutoDock Vina 1.5.6. Online log P predictions were also made possible by the Swiss ADME algorithm. PKCSM software was used to assess the potential toxicity of the leading compounds. Results: Auto Dock Vina 1.5.6 was used to dock 422 indole derivatives. Compounds with the greatest binding affinity to glucokinase (GK) were found in the majority of the compounds. Based on the superior binding capabilities of the top eight molecules compared to Dorzagliatin (the standard drug) and MRK (the co-crystallized ligand), the top eight molecules were chosen. Following the enhancement of their pharmacokinetic profiles and compliance with Lipinski';s rule of five, these eight candidates were further evaluated using ADMET analysis. As a result, AH249 displayed the greatest binding affinity with -11.5 kcal/mol. In contrast to the standard drugs Dorzagliatin (GKA) and MRK (co-crystallized ligand), AH249 showed no skin sensitization, AMES toxicity, or hepatotoxicity using PKCSM. Discussion: This research highlights the importance of in silico techniques in discovering antidiabetic medicines, as AH249 outperformed 421 other indole derivatives in terms of glucokinase affinity. According to SwissADME results, both compounds, AH249 and AH102, are drug-like. Analysis through molecular docking revealed interactions that can be tested and verified using experiments. Conclusion: There are 422 selected lead compounds containing an indole base in the 53,000 compound database that demonstrated the best activation of glucokinase among the 53,000 compounds. According to the findings of this computational drug design analysis, the most promising drug candidates deserve consideration for advancement to the in vitro stage, particularly AH249, which exhibits the greatest binding affinity, a favorable pharmacokinetic profile, and negligible toxicity. For a better understanding of the therapeutic implications of the drug, particularly within the field of type 2 diabetes, more thorough investigation and evaluation are essential, especially the use of in-vivo models such as Streptozotocin-induced diabetic rats.

In this study, we measured the inhibitory potential of six coumarins against aldose reductase using both computational and experimental approaches. Molecular docking, molecular dynamics simulations, and MM/PBSA binding free energy calculations identified auraptene, marmesin, and isopimpinellin as the most promising inhibitors, with binding affinities of ΔG = -34.88, -29.40, and -20.31 kcal/mol, respectively. ADMET analysis indicated favorable pharmacokinetic properties for all three compounds, including high gastrointestinal absorption and bioavailability. In vitro assays confirmed auraptene as the most potent inhibitor with the lowest IC50 (1.43 ± 0.14 µM), outperforming quercetin (IC50 = 2.50 ± 0.31 µM). Marmesin and isopimpinellin showed IC50 values of 3.80 ± 0.1 µM and 5.71 ± 0.8 µM, respectively. Kinetic studies revealed auraptene as a noncompetitive inhibitor (Ki = 1.84 µM), isopimpinellin as a competitive inhibitor (Ki = 1.83 µM), and marmesin as a mixed inhibitor (Ki = 2.32 µM). These results suggest auraptene and marmesin as potential lead compounds for AR inhibition with strong binding affinities and favorable pharmacokinetic profiles.

Matrix Metalloproteinases-9 (MMP-9) is one of the important targets that play a vital role in various diseases such as cancer, Alzheimer’s, arthritis, etc. Traditionally, MMP-9 inhibitors have been unable to achieve selectivity to get around this target; thereby, novel mechanisms such as inhibition of activated MMP-9 zymogen (pro-MMP-9) have been discovered. The JNJ0966 was one of the few compounds that attained the requisite selectivity by inhibiting the activation of MMP-9 zymogen (pro-MMP-9). Since JNJ0966, no other small molecules have been identified. Herein, extensive in silico studies were called upon to bolster the prospect of exploring potential candidates. The key objective of this research is to identify the potential hits from the ChEMBL database via molecular docking and dynamics approach. Protein with PDB ID: 5UE4, having a unique inhibitor in an allosteric binding pocket of MMP-9, was chosen for the study. Structure-based virtual screening and MMGBSA binding affinity calculations were performed, and five potential hits were finalized. Detailed analysis of the best-scoring molecules was performed with ADMET analysis and molecular dynamics (MD) simulation. All five hits outperformed JNJ0966 in the docking assessment, ADMET analysis, and molecular dynamics simulation. Accordingly, our research findings imply that these hits can be investigated for in vitro and in vivo studies against proMMP9 and might be explored as potential anticancer drugs. The outcome of our research might contribute in expediting the exploration of drugs that inhibits proMMP-9. Communicated by Ramaswamy H. Sarma

Candida albicans (C. albicans) is an opportunistic pathogen in immunocompromised individuals and a normal inhabitant of the oral cavity, throat, gastrointestinal tract, and genitourinary system among health populations. Our study focused on identifying new inhibitors capable of binding to the mutant cytochrome P450 family 51 (CYP-51) protein and intended to be effective against resistant C. albicans infections. The pharmacophore ligand-based model was used for the virtual screening of compound libraries. Molecular docking was performed on Maestro, Schrodinger. ADMET analysis was performed to check drug-likeness properties. Density function theory (DFT) calculations, molecular dynamic (MD) simulation, and free binding energy (MMPBSA) were also calculated. For docking, six compounds were selected from 11,022 hits from PubChem libraries, which showed the best interaction with mutant CYP-51 and were identified by pharmacophore mapping performed with the Pharma IT tool. Each of the six compounds was docked into the active site of the mutant CYP-51 protein. Overall, CP-3 exhibited significant binding affinity (-10.70 kcal/mol) as well as, showed good ADMET characteristics such as drug-likeness, absorption, distribution, metabolism, excretion, and toxicity. The lead compound, CP-3, was further used for MD simulation to observe the dynamic behavior of the complex in the active site of the mutant CYP-51 protein. Computational studies indicated that CP-3 could be a useful antagonist for the mutant protein, CYP-51. This study used computational approaches to identify potential inhibitors of C. albicans by targeting CYP-51 for antifungal drug development. Further invitro and in vivo studies are needed to evaluate its pharmacokinetic properties and efficacy as a novel antifungal drug.

Biofilm inhibition mechanism from extract of Hymenocallis littoralis leaves

Investigating mutations at the hotspot position of the ERBB2 and screening for the novel lead compound to treat breast cancer - a computational approach.

Gastrointestinal (GI) cancers are a significant global health concern with diverse etiologies and limited treatment options. Ellagic acid (EA), a natural polyphenolic compound, exhibits promising anticancer properties against various GI malignancies. In this article, we have reviewed recent research on the anticancer potential of EA across esophageal, gastric, colorectal, pancreatic, and liver cancers. In esophageal cancer, EA inhibits the formation of O6-methylguanine (O6-meGua) adducts induced by carcinogens like N-nitrosomethylbenzylamine (NMBA), thereby suppressing tumor growth. Additionally, EA inhibits STAT3 signaling and stabilizes tumor suppressor proteins, showing potential as an anti-esophageal cancer agent. In gastric cancer, EA regulates multiple pathways involved in cell proliferation, invasion, and apoptosis, including the p53 and PI3K-Akt signaling pathways. It also demonstrates anti-inflammatory and antioxidant effects, making it a promising therapeutic candidate against gastric cancer. In colorectal cancer (CRC), EA inhibits cell proliferation, induces apoptosis, and modulates the Wnt/β-catenin and PI3K/Akt pathways, suggesting its efficacy in preventing CRC progression. Furthermore, EA has shown promise in pancreatic cancer by inhibiting nuclear factor-kappa B, inducing apoptosis, and suppressing epithelial–mesenchymal transition. In liver cancer, EA exhibits radio-sensitizing effects, inhibits inflammatory pathways, and modulates the tumor microenvironment, offering potential therapeutic benefits against hepatocellular carcinoma. Studies on EA potential in combination therapies and the development of targeted delivery systems are required for enhanced efficacy against gastrointestinal cancers.

Ellagic acid (EA) is an antiplasmodial polyphenol with reported in-vitro activity against Plasmodium falciparum. Studies have reported that EA acts in the late erythrocytic stages of P. falciparum (Pf) when DNA synthesis is taking place. Pf dihydrofolate reductase-thymidylate synthase (PfDHFR-TS) is an important enzyme for DNA synthesis as its inhibition can kill the parasite. As there is no reported study on the molecular interactions between EA and PfDHFR-TS, we aim to study the molecular interactions between EA and PfDHFR-TS (PDB ID: 3DGA) through molecular docking, molecular dynamics (MD) simulations, binding free energy (MM-GBSA) calculations, and density functional theory (DFT) studies. Site-specific and blind docking revealed that EA has a high binding affinity for the active site of PfDHFR-TS. EA formed hydrogen bonds with multiple active site residues. MD simulations for 100 ns revealed that the PfDHFR-TS-EA complex was stable. The average binding free energy of the PfDHFR-TS-EA complex throughout the 100 ns MD simulations was −39.84 kcal/mol. The energy difference (ΔE = 0.04089 eV) obtained from DFT studies indicates the electrical stability and reactivity of EA at the active site of PfDHFR-TS. We conclude that the antiplasmodial activity of EA might be attributed to its ability to potentially bind with PfDHFR-TS.