Novel urushiol derivatives as HDAC8 inhibitors: rational design, virtual screening, molecular docking and molecular dynamics studies

Molecular insights of oxadiazole benzene sulfonamides as human carbonic anhydrase IX inhibitors: Combined molecular docking, molecular dynamics, and 3D QSAR studies

Design, synthesis, biological evaluation, molecular docking and QSAR studies of 2,4-dimethylacridones as anticancer agents

The ongoing quest for multifunctional organic molecules that exhibit both pharmaceutical and optoelectronic potential has intensified interest in heterocyclic compounds. Among them, hydrazone derivatives stand out for their diverse biological activities, including antimicrobial, antiviral, and anticancer properties, as well as their tunable electronic and optical properties. The presence of the –C N–NH– linkage enables effective conjugation and charge transfer, enhancing their chemical reactivity, stability, and nonlinear optical (NLO) behaviour. Owing to these versatile features, the design and synthesis of novel hydrazone-based heterocycles have gained prominence for potential applications in drug development and advanced material science. This study focuses on the design, synthesis, and characterization of a novel hydrazone derivative, N′-((2,3-dihydrobenzo[ b ][1,4]dioxin-6-yl)methylene)furan-2-carbohydrazide (DDMF). The compound combines furan and benzo dioxane moieties to enhance conjugation and biological activity. Its structural, electronic, and reactive properties were examined using FT-IR, ¹H NMR, ¹ ³C NMR, and DFT-based quantum chemical analyses. In addition, molecular docking and ADMET studies were performed to evaluate its binding affinity, drug-likeness, and pharmacokinetic behaviour, providing insight into its potential pharmaceutical and optoelectronic applications. The DDMF compound was synthesized and structurally confirmed using FT-IR, ¹H NMR, and ¹ ³C NMR spectroscopy. Theoretical investigations were carried out using Density Functional Theory (DFT) to study molecular geometry, electronic structure, and reactivity descriptors. Frontier Molecular Orbital (FMO), Natural Bond Orbital (NBO), and Molecular Electrostatic Potential (MEP) analyses were performed to assess charge distribution and reactive sites. In addition, UV-Vis, NLO, and molecular docking studies were conducted alongside ADMET and drug-likeness evaluations. The optimized geometry showed excellent correlation with experimental data, exhibiting minimal RMSD in bond lengths (0.020 Å) and bond angles (5.20°). FMO analysis revealed moderate reactivity and effective charge transfer, while NBO and MEP confirmed significant electron delocalization. The compound exhibited strong NLO activity and consistent NMR spectral agreement (¹H RMSD = 0.437 ppm; ¹³C RMSD = 1.24 ppm). UV-Vis spectra indicated distinct π→π* transitions at 275 and 350 nm. Docking studies showed stable interactions of DDMF with SARS-CoV-2 targets, supported by stable RMSD (∼1–2.5 Å) and low RMSF values. The compound demonstrated excellent intestinal absorption (94.63 %), favorable ADMET profiles, and high drug-likeness (MW 272.26 g/mol, LogP 1.84, TPSA 73.06 Ų). The combined experimental and theoretical investigations unequivocally confirm the successful synthesis, structural integrity, and stability of the DDMF molecule. The compound exhibits favorable electronic configuration, optical responsiveness, and pharmacological potential, as evidenced by its consistent spectroscopic characteristics, strong charge-transfer behaviour, and stable molecular interactions with biological targets. The integration of computational and spectroscopic analyses establishes DDMF as a structurally robust and functionally versatile molecule, making it a promising candidate for future advancements in both optoelectronic device fabrication and therapeutic drug development. • Synthesis of novel hydrazone derivative. • Investigation of electronic properties through DFT-based analysis. • Molecular docking analysis to evaluate the inhibitory potential of the synthesized compound. • Molecular dynamics simulation conducted over a 100 ns period to examine the dynamic interactions between the protein and ligand.

Although cancer continues to be one of the world’s major causes of death, current cancer drugs have many serious side effects. There remains a need for new anticancer agents to overcome these shortcomings. Alternaria is one of the most widespread fungal genera, many species of which produce several classes of metabolites with potential polypharmacological activities. A few quinones and pyrones from Alternaria spp. have proven to exert cytotoxic effects against certain cancer cell lines, but their molecular mode of action is not known. The current study aimed to investigate the potential mechanisms that underlie the anticancer activity of a few selected quinones and pyrones from Alternaria solani and Alternaria alternata by molecular docking and dynamic simulation approaches. The selected metabolites were screened for their binding affinity to Heat shock protein 90 (HSP90), which is a known anticancer drug target. Molecular docking studies have revealed that Macrosporin, Altersolanol B, Fonsecin, and Neoaltenuene have good binding affinities with the target protein and the stabilities of the formed complexes were evaluated through molecular dynamics simulations. By analyzing the Root Mean Square Distance (RMSD), Root Mean Square Fluctuation (RMSF), and Principal Component Analysis (PCA) plots obtained from molecular dynamics simulations, this study shows that the complexes of all 4 lead molecules with target protein are stable over a 100 ns period. Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations were used to compute the binding free energies. The lead molecules were studied using in-silico analysis to determine their drug-likeness based on their Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) and physicochemical properties. The results demonstrate that Macrosporin, Fonsecin, and Neoaltenuene could become promising anticancer molecules that target HSP90. Communicated by Ramaswamy H. Sarma

Ficus carica L., commonly known as fig, has been used in traditional medicine for metabolic disorders, cardiovascular diseases, respiratory diseases and cancer. Various bioactive compounds have been previously isolated from the leaves, fruit, and bark, which have different pharmacological properties, but the anticancer mechanisms of this plant are not known. In the current study we focused on understanding the probable mechanisms underlying the anticancer activity of F. carica plant extracts by molecular docking and dynamic simulation approaches. We evaluated the drug-likeness of the active constituents of the plant and explored its binding affinity with selected anticancer drug target receptors such as cyclin-dependent kinase 2 (CDK-2), cyclin-dependent kinase 6 (CDK-6), topoisomerase-I (Topo I), topoisomerase-II (Topo II), B-cell lymphoma 2 (Bcl-2), and vascular endothelial growth factor receptor 2 (VEGFR-2). In silico toxicity studies revealed that thirteen molecules out of sixty-eight major active compounds in the plant extract have acceptable drug-like properties. Compound 37 (β-bourbonene) has a good binding affinity with the majority of drug targets, as revealed by molecular docking studies. The complexes of the lead molecules with the drug receptors were stable in terms of molecular dynamics simulation derived parameters such as root mean square deviation and radius of gyration. The top ten residues contributing significantly to the binding free energies were deciphered through analysis of molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) and molecular mechanics generalized Born surface area (MM-GBSA). Thus, the results of our studies unravel the potential of F. carica bioactive compounds as anticancer candidate molecules against selected macromolecular receptors.

Background and aimThe discovery of drugs capable of inhibiting SARS-CoV-2 is a priority for human beings due to the severity of the global health pandemic caused by COVID-19. To this end, natural products can provide therapeutic alternatives that could be employed as an effective safe treatment for COVID-19. Experimental procedureTwelve compounds were isolated from the aerial parts of C. officinalis L. and investigated for their inhibitory activities against SARS-CoV-2 Mpro compared to its co-crystallized N3 inhibitor using molecular docking studies. Furthermore, a 100 ns MD simulation was performed for the most active two promising compounds, Calendulaglycoside A (SAP5) and Osteosaponin-I (SAP8). Results and conclusionAt first, molecular docking studies showed interesting binding scores as compared to the N3 inhibitor. Calendulaglycoside A (SAP5) achieved a superior binding than the co-crystallized inhibitor indicating promising affinity and intrinsic activity towards the Mpro of SARS-CoV-2 as well. Moreover, findings illustrated preferential stability for SAP5 within the Mpro pocket over that of N3 beyond the 40 ns MD simulation course. Structural preferentiality for triterpene-Mpro binding highlights the significant role of 17β-glucosyl and carboxylic 3α-galactosyl I moieties through high electrostatic interactions across the MD simulation trajectories. Furthermore, this study clarified a promising SAR responsible for the antiviral activity against the SARS-CoV-2 Mpro and the design of new drug candidates targeting it as well. The above findings could be promising for fast examining the previously isolated triterpenes both pre-clinically and clinically for the treatment of COVID-19.

Herbal plants are often used as alternative medicine because they contain active compounds for the treatment of diseases and disorders with minimal side effects, and are easily obtained from the surrounding environment. Some of them have antiviral activity. This study aimed to analyze the potential of phytochemical compounds in the leaf of “pangi” (Pangium edule Reinw) as antiSARS-CoV-2 using molecular docking study. The drug- and lead-likeness properties of the selected compounds were obtained from the Swiss ADME and admetSAR online server tools. Molecular dynamics (MD) simulation of the selected ligand was carried out to validate the stability of the interaction. The results suggested that pangi leaves contain three compounds with remarkable binding affinities with Mpro (main protease) and RBD (receptor binding domain) were (5.beta.) pregnane-3,20.beta.-diol, 14.alpha.,18.alpha.-[4-methyl-3-oxo-(1-oxa-4-azabutane-1,4-diyl)]-, diacetate (PD), ethyl cholate (EC), and bis(3,5,5-trimethylhexyl) phthalate. Because EC will be metabolized in the body into cholic acid (Cho), this compound was then docked and validated using MD simulation. The compound has the best free binding energy (ΔG) with SARS-CoV-2 (–7.1 kcal/ mol with Mpro and –6.0 kcal/mol with RBD). Moreover, the compound is bound strongly to the active cavity of Mpro on Thr24, Thr26, His41, and Cys145 residues. The MM-GBSA calculation showed that the interaction of Cho with Mpro was higher than with RBD. According to the RMSD (root mean square deviation), RMSF (root mean square fluctuation), the radius of gyration (Rg), and intermolecular hydrogen bond (H-bond) analysis obtained from 50 ns MD simulations, Cho formed stable interactions with Mpro and RBD. The finding of this study indicated that Cho showed good anti-SARS-CoV-2 activity. The potential of the compound to inhibit the virus can serve as a starting point in the process of developing COVID-19 therapeutic natural medicine.

The main objective of this research is to identify potential leads for developing potent Keap1 inhibitors. In the current research article, in-silico methods have been employed to discover potential Keap1 inhibitors. 3D-QSAR was generated using the ChemBL database of Keap1 inhibitors with IC50. The best pharmacophore was selected for the screening of three different libraries namely Asinex, MiniMaybridge, and Zinc. The molecules screened from the databases were filtered through druggability rules and molecular docking studies. The best binding molecules obtained after docking studies were subjected to physicochemical properties toxicity determination by in-silico methods. The best hits were studied for stability in the cavity of Keap1 by molecular dynamic simulations. The virtual screening of different databases was carried out separately and three leads, were obtained. These lead molecules ASINEX 508, MiniMaybridgeHTS_01719, and ZINC 0000952883 showed the best binding in the Keap1 cavity. The molecular dynamic simulations of the binding complexes of the leads support the docking analysis. The leads (ASINEX 508, MiniMaybridgeHTS_01719, and ZINC 0000952883) were stabilized in the Keap1 binding cavity throughout 100 ns simulation, with average RMSD values of 0.100, 0.114, and 0.106 nm, respectively. This research proposes three lead molecules as potential Keap1 inhibitors based on high throughput screening, docking, and MD simulation studies. These hit molecules can be used for further design and development of Keap1 inhibitors. This research provides the preliminary data for discovering novel Keap1 inhibitors. It opens new avenues for medicinal chemists to explore antioxidant-stimulating molecules targeting the Keap1-Nrf2 pathway.

Lophosoria quadripinnata (J.F.Gmel.) C.Chr., a fern species from the Dicksoniaceae family, is widely distributed in Central and South America. This study aimed to identify the bioactive compounds in the aqueous extract of L. quadripinnata, evaluate its antioxidant potential through in vitro analysis, and assess its neuroprotective effects via molecular docking and dynamics studies. Fourteen compounds were identified using ultra-high-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-ESI-QToF-MS). In vitro assays revealed high concentrations of phenolic and flavonoid compounds, alongside significant antioxidant activity. Molecular docking studies, involving acetylcholinesterase (AChE), butyrylcholinesterase (BChE), tyrosinase, and the Nrf2-Keap1 protein complex, identified three compounds-5C3M (5-O-caffeoyl-3-O-malonylquinic acid), 5GDC (5-O-glucoside-6,7-dimethoxycoumarin), and irifloside-as promising inhibitors. These compounds exhibited favorable binding affinities, minimal toxicity, and strong interactions with key residues involved in the inhibition of the enzymes and protein complex. Additionally, molecular dynamics simulations revealed stable binding with AChE, BChE, and tyrosinase, with irifloside showing the highest binding affinity. The compounds also demonstrated the ability to modulate the Nrf2-Keap1 pathway, potentially enhancing the cellular antioxidant response. These findings suggest that L. quadripinnata contains bioactive compounds with significant potential for the development of neuroprotective agents, especially in oxidative stress-related diseases such as Alzheimer's and Parkinson's.

Alzheimer’s disease (AD) is the most devastating neurodegenerative disorder which alters the memory of a person. It is a common form of senile dementia characterized by memory loss, personal skills and disorientation. The current treatment for AD is fully focused to control the disease based on symptoms. Based on the tau hypothesis, GSK3β is an interesting drug target, this also alters the course of AD. The recent experimental report outlines that the indirubin derivatives inhibit GSK3β, however, the detailed binding mechanism of indrubin-GSK3β is not yet known. To understand the exact binding mechanism of indirubin derivatives in the active site of GSK3β, the molecular conformation, intermolecular interactions, charge density distribution, electrostatic properties and the stability were determined. To accomplish this, indirubin derivatives were screened via molecular docking and further molecular dynamics (MD) and QM/MM-based charge density analysis have been performed. The molecular docking was carried out to investigate the binding affinity and the intermolecular interactions of indirubin molecule in the active site of GSK3β. QM/MM based charge density (CD) analysis has been carried out to emphasize the nature of chemical bonding (topology of electron density) and the electrostatic properties of ligand in the binding pocket. We have performed the CD analysis of intermolecular interaction between indirubin-3-monoxime and the active site amino acids of GSK3β. Further, the stability of the molecule has been confirmed from the MD simulation and the binding free energy of the indirubin-3-monoxime-GSK3β complex has been determined using MM/PBSA method to validate the binding affinity of indirubin-3-monoxime.Communicated by Ramaswamy H. Sarma

Novel bodipy-calix[4]arene fluorophores: DNA interaction, spectroscopic properties, electrophorese and molecular docking

The study aimed to screen prospective molecular targets of BCC and potential natural lead candidates as effective binders by computational modeling, molecular docking, and dynamic (MD) simulation studies. Based on the virulent functions, tRNA 5-methylaminomethyl-2-thiouridine biosynthesis bifunctional protein (mnmC) and pyrimidine/purine nucleoside phosphorylase (ppnP) were selected as the prospective molecular targets. In the absence of experimental data, the three-dimensional (3D) structures of these targets were computationally predicted. After a thorough literature survey and database search, the drug-likeness, and pharmacokinetic properties of 70 natural molecules were computationally predicted and the effectual binding of the best lead molecules against both the targets was predicted by molecular docking. The stabilities of the best-docked complexes were validated by MD simulation and the binding energy calculations were carried out by MM-GBSA approaches. The present study revealed that the hypothetical models of mnmC and ppnP showed stereochemical accuracy. The study also showed that among 70 natural compounds subjected to computational screening, Honokiol (3',5-Di(prop-2-en-1-yl) [1,1'-biphenyl]-2,4'-diol) present in Magnolia showed ideal drug-likeness, pharmacokinetic features and showed effectual binding with mnmC and ppnP (binding energies -7.3kcal/mol and -6.6kcal/mol, respectively). The MD simulation and GBSA calculation studies showed that the ligand-protein complexes stabilized throughout tMD simulation. The present study suggests that Honokiol can be used as a potential lead molecule against mnmC and ppnP targets of BCC and this study provides insight into further experimental validation for alternative lead development against drug resistant BCC.

Kinesin Eg5 plays an essential role in the early stages of mitosis, and it is an interesting drug target for the design of potent inhibitors. In this work, combined molecular modeling studies of molecular docking, receptor-guided QSAR methodology, and molecular dynamics (MD) simulation were performed on a series of novel S-trityl-l-cysteine (STLC) analogues as Eg5 inhibitors to understand the structural features and key residues which are involved in the inhibition. Molecular docking study was used to find the actual conformations of STLC analogues in the binding site of Eg5. Multiple linear regression (MLR), artificial neural network (ANN), and support vector machine (SVM) models were developed by the conformation which was obtained by performing docking studies. The satisfactory result of the SVM model (R2 = 0.962, SE = 0.210, RMSE = 0.190, and Q2LOO = 0.930) demonstrated the superiority of this model over other models. Also, the satisfactory agreement between experiment and predicted inhibitory values suggested that the SVM model represents good correlation and predictive power. Molecular docking was used to study the functionalities of active molecular interaction between inhibitors and Eg5. Moreover, molecular dynamics (MD) simulation was performed on the best inhibitor-Eg5 complex to investigate the stability of docked conformation and to study the binding interactions in detail. The MD simulation result showed four hydrogen bond interactions with Eg5 residues including Gly117, Glu116, Gly117, and Glu118. The outcome of this study can be used as a guideline to better interpret the protein-ligand interaction and also can assist in the designing and development of more potent Eg5 inhibitors.

Synthesis, characterization, and biological activities of novel organometallic compounds of rhenium(I) with 2-(2-benzylidenehydrazinyl) benzothiazole Schiff-base derivatives: Molecular docking, ADME, and DFT studies.

Synthesis, structure, DNA/protein molecular docking and biological studies of hydrazone ligand derived Cu(II) and VO(IV) complexes