Development of novel CDK9 and CYP3A4 inhibitors for cancer therapy through field and computational approaches.

Cyclin-dependent kinase 9 (CDK9) and cytochrome P450 3A4 (CYP3A4) have emerged as promising targets in the development of anticancer drugs, presenting a consistent challenge in the quest for potent inhibitors. CDK9 inhibitors can selectively target fast-growing cancer cells by disrupting transcription elongation, which in turn hinders the production of proteins essential for cell cycle progression and survivaS. Understanding how CYP3A4 metabolizes specific chemotherapy drugs allows for personalized treatment plans, optimizing drug dosages according to a patient's metabolic profile. Since many cancer patients undergo combination therapies, and CYP3A4 is vital in drug metabolism, its inhibition or induction by one drug can alter the plasma levels of others, potentially leading to treatment failure or increased toxicity. Therefore, managing CYP3A4 activity is critical for effective cancer treatment. Employing a range of computational methodologies, this study systematically investigated the binding mechanisms of pyrimidine derivatives against CDK9 and CYP3A4. The field-based model demonstrated high R 2 values (0.99), with Q2 (0.66), demonstrating its ability to predict in silico inhibitory activity against the target of this study. The screening process followed in this work led to the discovery of powerful new inhibitor compounds. Of the 15 new compounds designed, three have a high affinity with the target (ranging from -8 to -9 kcal/mol kcal/mol) and were singled out through docking filtration for more detailed investigation. As well as, a reference compound with a substantial pIC50 value of 8.4, serving as the foundation for the development of the new compounds, was included for comparative analysis. To elucidate the essential features of CDK9 and CYP3A4 inhibitor design, a comparative analysis was conducted between 3D-QSAR-generated contours and molecular docking conformations of ligands. Molecular dynamics simulations were carried out for a duration of 100 ns on selected docked complexes, specifically those involving novel compounds with CDK9 and CYP3A4 enzymes. Additionally, the binding free energy for these complexes was assessed using the MM/PBSA method, which evaluates the free energy landscape of protein-ligand interactions. The results of MM/PBSA highlighted the strength of the new compounds in enhancing interactions with the target protein, which favors the results of molecular docking and MD simulation. These insights contribute to a deeper understanding of the mechanisms underlying CDK9 and CYP3A4 inhibition, offering potential avenues for the development of innovative and effective CDK9 inhibitors.

Impact of molecular structure on the biological removal efficiency of fluoroquinolone antibiotics: An in-silico approach.

Fluoroquinolone antibiotics (FQs), one of the most widely used antibacterials, have been recognized as emerging contaminants with adverse human health concerns. To overcome the adverse effects, a theoretical molecular design and screening approach was developed in this study to improve the removal efficiency of FQs by Chlorella in artificial or natural wetland systems. Among the 189 designed norfloxacin (NOR) derivatives, NOR-140 was screened with significantly improved biosorption, bioaccumulation, and biodegradation removal and functional effects, and reduced human health and ecological risks. The removal mechanism NOR-140 was also analyzed using adsorption kinetics, molecular docking, molecular dynamics simulations and machine learning models. Protein and polysaccharide structures play a major role in the adsorption process, polarizability and molecular volume of NOR-140 affect the bioaccumulation ability, and hydrogen bonding was found as the key force promoting the degradation ability of NOR-140. Modifying specific sites (5, 8, and 13) with functional groups containing highly electronegative atoms (O, F) significantly enhances the biodegradability of FQs alternatives by Chlorella. This study provided theoretical support for designing environmentally friendly FQs alternatives with improved degradation ability and advanced the understanding of how the FQs' molecular structures affect its removal by Chlorella.

Exploring characteristic features for effective HCN1 channel inhibition using integrated analytical approaches: 3D QSAR, molecular docking, homology modelling, ADME and molecular dynamics.

Neuropathic pain (NP) is characterized by hyperalgesia, allodynia, and spontaneous pain. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channel involved in neuronal hyperexcitability, has emerged as an important target for the drug development of NP. HCN channels exist in four different isoforms, where HCN1 is majorly expressed in dorsal root ganglion having an imperative role in NP pathophysiology. A specific HCN1 channel inhibitor will hold the better potential to treat NP without disturbing the physiological roles of other HCN isoforms. The main objective is to identify and analyze the chemical properties of scaffolds with higher HCN1 channel specificity. The 3D-QSAR studies highlight the hydrophobic & hydrogen bond donor groups enhance specificity towards the HCN1 channel. Further, the molecular interaction of the scaffolds with the HCN1 pore was studied by generating an open-pore model of the HCN1 channel using homology modelling and then docking the molecules with it. In addition, the important residues involved in the interaction between HCN1 pore and scaffolds were also identified. Moreover, ADME predictions revealed that compounds had good oral bioavailability and solubility characteristics. Subsequently, molecular dynamics simulation studies revealed the better stability of the lead molecules A7 and A9 during interactions and ascertained them as potential drug candidates. Cumulative studies provided the important structural features for enhancing HCN1 channel-specific inhibition, paving the way to design and develop novel specific HCN1 channel inhibitors.

Rational design and discovery of novel hydrazide derivatives as potent succinate dehydrogenase inhibitors inspired by natural d/l-camphor.

BACKGROUND: Succinate dehydrogenase inhibitors (SDHIs) have rapidly become one of the fastest-growing categories of fungicides used against plant pathogenic fungi. Recent research advancements have emphasized that structural modifications of SDHIs using naturally sourced scaffolds represent an innovative strategy for developing new, highly effective, broad-spectrum fungicides. A novel series of d/l-camphorhydrazide derivatives potentially targeting fungal succinate dehydrogenase (SDH) were designed, synthesized and evaluated for their antifungal effects against Rhizoctonia solani, Fusarium graminearum, Valsa mali and Botrytis cinerea. RESULTS: Amongst them, compounds A1-7 (d-camphor) and A2-7 (l-camphor) displayed excellent in vitro activity against R. solani with median effective concentration (EC50) values of 0.38 and 0.48 µg mL-1, which were obviously superior to that of boscalid (0.87 µg mL-1). A2-5 (l-camphor, EC50 = 3.27 µg mL-1) exhibited good activity against V. mali. A2-7 (2.13 µg mL-1), A2-21 (5.2 µg mL-1) and A1-5 (5.15 µg mL-1) showed good antifungal activity against F. graminearum with EC50 values below that of boscalid (5.85 µg mL-1). Preliminary mechanistic studies, using scanning and transmission electron microscopy, indicated that compound A1-7 induced disordered entanglement of hyphae, shrinkage of hyphal surfaces, and vacuole swelling and rupture, which disrupted normal hyphal growth. Additionally, compound A1-7 induced the production and accumulation of reactive oxygen species, disrupted mitochondrial membrane potential, and effectively inhibited the germination and formation of sclerotia in R. solani. Moreover, the molecular docking results and SDH enzyme assays yielded promising outcomes. CONCLUSION: In this study, the designed and optimized compounds A1-7 and A2-7 emerged as promising candidates for SDH-targeting fungicides, demonstrating strong antifungal activity. These compounds hold potential as new antifungal agents for further research. © 2024 Society of Chemical Industry.

Molecular docking, network pharmacology, and QSAR modelling studies of benzo[c]phenanthridines - novel antileishmaniasis agents.

Leishmaniasis treatment primarily relies on chemotherapy due to lack of vaccines. However, the low efficacy, parasite resistance, and toxicity associated with existing drugs necessitate the development of effective and safer therapies. Fuchino et al. reported promising leishmanicidal activity in a series of benzo[c]phenanthridines against L. major promastigotes. To progress these compounds towards drug development, it is crucial to understand their molecular targets, mechanisms of action, binding interactions, and structural requirements. In this research, molecular docking, network pharmacology, 2D-QSAR, and 3D-QSAR CoMFA studies were performed on 30 benzo[c]phenanthridines. Docking analysis showed that all molecules had a strong binding affinity to L. major-nucleoside diphosphate kinase (NDPK) compared to the other targets. 10-isopropoxy sanguinarine had the highest binding affinity (-10.6 kcal/mol) and formed ionic and hydrophobic interactions. Network pharmacology analysis of the most active compounds identified serine/threonine-protein kinase Mtor as a potential antileishmaniasis target in humans for benzo[c]phenanthridines. This was confirmed with high-affinity scores > -7.0 kcal/mol for all the compounds docked. GO and KEGG pathway enrichment identified Reg. of fatty acid oxidation (BP), TORC1 complex (CC), RNA polymerase III type 1 promoter sequence-specific DNA binding (MF), and Acute myeloid leukemia (KEGG pathway) to be highly enriched with the hub genes. Both 2D and 3D-QSAR CoMFA models satisfied the internal and external validation tests as follows: 2D-QSAR: R2Train = 0.9040, Q2cv = 0.8648, R2adj = 0.8838, and R2Test = 0.8740; and 3D-QSAR: r2 = 0.998, q2 = 0.526, and SDEP = 0.856. The molecules can be practically evaluated as superior antileishmaniasis agents.

Xanthine oxidase inhibitors: Virtual screening and mechanism of inhibition studies.

Xanthine oxidase (XO), which plays a key role in purine metabolism, is an important target enzyme for the prevention and treatment of hyperuricemia. Inhibitory activity against XO is a common criterion for the screening of compounds with potential anti-hyperuricemic activity. In this study, 22 XO inhibitors were used to construct a 3D-QSAR pharmacophore model. Subsequently, molecular docking and in vitro activity evaluations were used to identify strong XO inhibitors from a list of 2000 natural compounds. The interaction mechanisms of these compounds with XO were analyzed based on inhibition kinetics and multi-spectral analyses. The pharmacophore model was composed of three hydrogen bond receptors and a hydrophobic center. The screened compounds - Diosmetin, Fisetin, and Genistein - all showed good XO inhibitory activity, with IC50 values of 1.86 ± 0.11 µM, 5.83 ± 0.08 µM, and 7.56 ± 0.10 µM, respectively. Kinetic analysis, fluorescence quenching assays, and molecular docking experiments showed that Diosmetin, Fisetin, and Genistein docked near the same active site of XO, mainly affecting the microenvironment of tryptophan residues. These molecules showed static binding to XO via hydrogen bonds, hydrophobic interactions, and van der Waals forces. Diosmetin and Genistein were competitive inhibitors, whereas Fisetin was a mixed inhibitor. Infrared spectroscopy showed that Diosmetin, Fisetin, and Genistein increased the α-helix content of XO from 7.4 % to 16.6 %, 21.4 %, and 11.2 %, respectively, thereby enhancing its stability. In summary, the pharmacophore model constructed in this study was accurate. The flavonoids Diosmetin, Fisetin, and Genistein effectively inhibited the activity of XO, and the amino acid residues LEU257, ILE353, and VAL259 played a key role in the interaction between the flavonoids and XO. These findings are of great significance for the screening and development of new XO inhibitors.

Development of Novel ROCK Inhibitors via 3D-QSAR and Molecular Docking Studies: A Framework for Multi-Target Drug Design.

Background/Objectives: Alterations in the actin cytoskeleton correlates to tumor progression and affect critical cellular processes such as adhesion, migration and invasion. Rho-associated coiled-coil-containing protein kinases (ROCK1 and ROCK2), important regulators of the actin cytoskeleton, are frequently overexpressed in various malignancies. The aim of this study was therefore to identify the key structural features of ROCK1/ROCK2 inhibitors using computer-aided drug design (CADD) approaches. In addition, new developed ROCK inhibitors provided a significant framework for the development of multitarget therapeutics-ROCK/HDAC (histone deacetylases) multitarget inhibitors. Methods: 3D-QSAR (Quantitative structure-activity relationship study) and molecular docking study were employed in order to identify key structural features that positively correlate with ROCK inhibition. MDA-MB-231, HCC1937, Panc-1 and Mia PaCa-2 cells were used for evaluation of anticancer properties of synthesized compounds. Results: C-19 showed potent anti-cancer properties, especially enhancement of apoptosis and cell cycle modulation in pancreatic cancer cell lines. In addition, C-19 and C-22 showed potent anti-migratory and anti-invasive effects comparable to the well-known ROCK inhibitor fasudil. Conclusions: In light of the results of this study, we propose a novel multi-target approach focusing on developing dual HDAC/ROCK inhibitors based on the structure of both C-19 and C-22, exploiting the synergistic potential of these two signaling pathways to improve therapeutic efficacy in metastatic tumors. Our results emphasize the potential of multi-target ROCK inhibitors as a basis for future cancer therapies.

Integration of 3D-QSAR, molecular docking, and machine learning techniques for rational design of nicotinamide-based SIRT2 inhibitors.

Selective inhibitors of sirtuin-2 (SIRT2) are increasingly recognized as potential therapeutics for cancer and neurodegenerative diseases. Derivatives of 5-((3-amidobenzyl)oxy)nicotinamides have been identified as some of the most potent and selective SIRT2 inhibitors reported to date (​Ai et al., 2016​; ​Ai et al., 2023​, ​Baroni et al., 2007​). In this study, a 3D-QSAR (3D-Quantitative Structure-Activity Relationship) model was developed using a dataset of 86 nicotinamide-based SIRT2 inhibitors from the literature, along with GRIND-derived pharmacophore models for selected inhibitors. External validation parameters emphasized the reliability of the 3D-QSAR model in predicting SIRT2 inhibition within the defined applicability domain. The interpretation of the 3D-QSAR model facilitated the generation of GRIND-derived pharmacophore models, which in turn enabled the design of novel SIRT2 inhibitors. Furthermore, based on molecular docking results for the SIRT1-3 isoforms, two classification models were developed: a SIRT1/2 model using the Naive Bayes algorithm and a SIRT2/3 model using the k-nearest neighbors algorithm, to predict the selectivity of inhibitors for SIRT1/2 and SIRT2/3. External validation parameters of the selectivity models confirmed their predictive power. Ultimately, the integration of 3D-QSAR, selectivity models and prediction of ADMET properties facilitated the identification of the most promising selective SIRT2 inhibitors for further development.

Discovery of Daclatasvir as a potential PD-L1 inhibitor from drug repurposing.

This study employed a drug repositioning strategy to discover novel PD-L1 small molecule inhibitors. 3D-QSAR pharmacophore models were establishedand subsequently validated through various means to select a robust model, Hypo-1, suitable for virtual screening. Hypo1 was used toscreen a library of 7,475 compounds from the Drugbank database, leading to the identification of 283 molecules following molecular docking with PD-L1.19 compounds underwent HTRF assays, with 15 showing varying degrees of inhibition of the PD-1/PD-L1 interaction. Compounds2202,2204,2207, and2208were further confirmed to bind to PD-L1 using SPR experiments. Among them, compound2204(Daclatasvir, KD = 11.4 µM) showeda higher affinity for human PD-L1 than the control compound BMS-1. In the HepG2/Jurkat cell co-culture model, Daclatasvir effectively activated Jurkat cells to kill HepG2 cells. In the mouse H22 hepatocellular tumor model, Daclatasvir significantly inhibited tumor growth (TGI = 53.4 % at a dose of 100 mg/kg). Its anti-tumor effect was more pronounced when combined with Lenvatinib (TGI = 85.1 %). Flow cytometry analysis of splenocytes and tumor cells indicated that Daclatasvir activated the immune system in both models. In summary, Daclatasvir was identified as a novel PD-L1small molecule inhibitor.

Novel "Phenyl-Pyrazoline-Oxadiazole" Ternary Substructure Derivatives: Synthesis, Insecticidal Activities, and Structure-Activity Relationship Study.

In recent years, isoxazole insecticides or parasiticides targeting the γ-aminobutyric acid receptor, such as fluralaner or fluxametamide, featured a novel chemical structure and exhibited potent insecticidal activity with no-cross resistance. Thus, many research institutes have tried to modify the structures of these agents to find a new insecticide. Previously, the majority of researchers stuck to the "phenyl-isoxazole-phenyl" structure, making modifications only to other components. In this study, the "phenyl-isoxazole-phenyl" ternary motif was modified for the first time based on bioisosterism theory. A series of new derivatives carrying pyrazoline and 1,3,4-oxadiazole moieties were designed and synthesized to investigate their insecticidal activities against the diamondback moth (Plutella xylostella) and fall armyworm (Spodoptera frugiperda). Preliminary bioassay data showed that some of the target compounds exhibited good insecticidal activities against P. xylostella and S. frugiperda. Especially, compound A21 showed insecticidal activity against P. xylostella (LC50 = 1.2 µg/mL) better than commercial insecticide ethiprole (LC50 = 2.9 µg/mL) but worse than parasiticide fluralaner (LC50 = 0.5 µg/mL). Similarly, compound A21 exhibited insecticidal activity to S. frugiperda (LC50 = 13.2 µg/mL) better than commercial insecticide fipronil (LC50 = 78.8 µg/mL) but worse than fluralaner (LC50 = 0.7 µg/mL). Compound A21 could serve as a potential lead compound to control P. xylostella and S. frugiperda. The three-dimensional quantitative structure-activity relationship model revealed that the further introduction of an electron-donating group in the 2- or 3-site may increase the insecticidal activity of A21. Molecular dynamics simulations showed that the hydrogen bond of A21 and receptor was important for the binding receptor. This study has identified a new substructure called "phenyl-pyrroline-oxadiazole" instead of the previously known "phenyl-isoxazole-phenyl" substructure, offering a useful guide for the design of novel insecticide molecules.

Synthesis, pharmacological evaluation, and modeling of novel quaternary ammonium salts derived from ß-carboline containing an imidazole moiety as angiogenesis inhibitors.

In this study, a series of novel ß-carboline condensed imidazolium derivatives (7a-7y) were designed and synthesized by incorporating imidazolium salt structures into ß-carboline. The cytotoxicity of compounds 7a-7y was evaluated in various cancer cell lines, including lung cancer (A549), gastric cancer (BGC-823), mouse colon cancer (CT-26), liver cancer (Bel-7402), and breast cancer (MCF-7), using the MTT assay. Most compounds exhibited significant activity against one or more of the cancer cell lines. Notably, compounds 7 g, 7o, 7r, 7 s, 7u, 7v, 7x, and 7w showed the highest cytotoxic activity (IC50 < 2 µM) in the tested tumor cell lines. Compound 7x demonstrated cytotoxic activities of 1.3 ± 0.3 µM (for BGC-823), 2.4 ± 0.4 µM (against A549), 7.8 ± 0.9 µM (for Bel-7402), and 9.8 ± 1.4 µM (against CT-26). The chick chorioallantoic membrane assay revealed significant anti-angiogenic potential of compound 7x. Molecular imprinting studies suggested the anti-angiogenic effect of compound 7x might be attributed to inhibition of VEGFR2 kinase. Molecular docking and molecular dynamics further indicate that its activity may be primarily associated with the potential inhibition of VEGFR2. Our research outcomes have provided valuable lead compounds for the development of novel antitumor drugs and have offered beneficial insights for subsequent drug design and optimization.

Pharmacophore-based 3D-QSAR modeling, virtual screening, docking, molecular dynamics and biological evaluation studies for identification of potential inhibitors of alpha-glucosidase.

CONTEXT: Alpha-glucosidase enzyme is considered an important therapeutic target for controlling hyperglycemia associated with type 2 diabetes. Novel scaffolds identified as potential alpha-glucosidase inhibitors from the Maybridge library utilizing pharmacophore modeling, molecular docking and biological evaluation are reported in this manuscript. METHOD: A total of 51 xanthone series scaffolds previously reported as alpha-glucosidase inhibitors were collected and used as training and test sets. These sets were employed to develop and validate a pharmacophore-based 3D-QSAR model with statistically meaningful results using Schrodinger software. The model showed a high F value (F, 80.1) at five component partial least square factors, a high cross-validation coefficient (Q2, 0.66) and a good correlation coefficient (R2, 0.95). Pearson correlation coefficient (r) of 0.8400 indicated a greater degree of confidence in the model. Subsequently, virtual screening was performed with PHASE module of Schrodinger software using the above model to identify novel alpha-glucosidase inhibitors, and mapped compounds were evaluated for their interactions with the protein. The X-ray co-crystallised structure of the alpha-glucosidase protein in complex with acarbose (PDB Code: 5NN8) was used for molecular docking analysis using GLIDE module and a total of eight compounds were further selected for biological evaluation. Molecular dynamics analysis using GROMACS software was performed in the active site of alpha-glucosidase protein to gain insights into binding mechanism of the four active compounds which were finally found to exhibit inhibitory activity in the biological assay.

Identification of novel RANKL inhibitors through in silico analysis.

Receptor activator of nuclear factor-κB ligand (RANKL) is considered the principal regulator of osteoclast differentiation. Therefore, strategies interfering with the RANKL-RANK signaling pathway may effectively inhibit osteoclast differentiation and mitigate bone resorption. Consequently, RANKL has become a promising target for new drug design strategies. Despite extensive research on specific drugs and antibodies, only a few have shown efficacy in treating osteoporosis. To address this challenge, we aimed to explore new approaches for designing drugs for osteoporosis. In this study, a 3D quantitative structure-activity relationship (QSAR) pharmacophore model was built for RANKL with reference to known inhibitor IC50 values. The optimal pharmacophore model was then employed as a 3D query to screen databases for novel lead compounds. The obtained compounds were subjected to ADMET and TOPKAT analyses to predict drug pharmacokinetics and toxicity. Molecular docking and de novo evolution approaches were applied to verify the docking binding affinities of the compounds. Five candidate compounds were subjected to further in vitro analyses to assess their anti-osteoporotic effects, among which compound 4 demonstrated significant inhibitory activity, achieving an inhibitory rate of 92.6 % on osteoclastogenesis at a concentration of 10 µM. Subsequent molecular dynamics (MD) simulations to assess the stability and behavior of compound 4 and its evolved variant, ZINC00059014397_Evo, within the RANKL binding site revealed that the variant is a potential therapeutic agent for targeting osteoclasts. This study offers valuable insights for developing next generation RANKL inhibitors for osteoporosis treatments.

Robustaflavone as a novel scaffold for inhibitors of native and auto-proteolysed human neutrophil elastase.

Human neutrophil elastase (HNE) plays a key role in initiating inflammation in the cardiopulmonary and systemic contexts. Pathological auto-proteolysed two-chain (tc) HNE exhibits reduced binding affinity with inhibitors. Using AutoDock Vina v1.2.0, 66 flavonoid inhibitors, sivelestat and alvelestat were docked with single-chain (sc) HNE and tcHNE. Schrodinger PHASE v13.4.132 was used to generate a 3D-QSAR model. Molecular dynamics (MD) simulations were conducted with AMBER v18. The 3D-QSAR model for flavonoids with scHNE showed r2 = 0.95 and q2 = 0.91. High-activity compounds had hydrophobic A/A2 and C/C2 rings in the S1 subsite, with hydrogen bond donors at C5 and C7 positions of the A/A2 ring, and the C4' position of the B/B1 ring. All flavonoids except robustaflavone occupied the S1'-S2' subsites of tcHNE with decreased AutoDock binding affinities. During MD simulations, robustaflavone remained highly stable with both HNE forms. Principal Component Analysis suggested that robustaflavone binding induced structural stability in both HNE forms. Cluster analysis and free energy landscape plots showed that robustaflavone remained within the sc and tcHNE binding site throughout the 100 ns MD simulation. The robustaflavone scaffold likely inhibits both tcHNE and scHNE. It is potentially superior to sivelestat and alvelestat and can aid in developing therapeutics targeting both forms of HNE.

Synthesis, antifungal activity, and 3d-QSAR study of L-carvone-based pyrazole-oxime ester compounds.

Natural products can provide versatile substructures with potential bioactivity and biocompatibility for exploring bioactive compounds. Herein, to explore novel natural product-derived antifungal agents, 21 unreported L -carvone-based pyrazole-oxime ester compounds 6a-6u were synthesised using L-carvone as raw material, and structurally characterised by means of FT-IR,1H NMR,13C NMR, and HRMS. The results of the in vitro bioactivity tests showed that the target compounds exhibited certain antifungal activity against the eight tested plant fungi at the concentration of 50 mg/L, especially for Physalospora piricola. The inhibition rates of compounds 6e (R = m-Cl) and 6c (R = m-F) against P. piricola were 88.3% and 83.9%, respectively, both better than that of the positive control chlorothalonil. Compound 6e (R= m-Cl) with the most significant antifungal activity deserves further investigation as the potential leading compound. In addition, the structure-activity relationships (SARs) of the target compounds were investigated by establishing an effective three-dimensional quantitative structure-activity relationship (3D-QSAR) model.

Design, synthesis, evaluation, pharmacophore modeling, and 3D-QSAR of lappaconitine analogs as potential analgesic agents.

Alleviating pain is crucial for patients with various diseases. This study aimed to enhance the analgesic properties of lappaconitine, a natural drug, through structural modifications. Specifically, carbamate analgesic active fragments were innovatively introduced at multiple sites on the benzene ring of lappaconitine. A total of 53 lappaconitine analogs were synthesized and evaluated. Compounds 5a, 5c, 5e, 6, and 15j addressed the narrow therapeutic window of lappaconitine, enhancing drug safety. Notably, carbamate analogs exhibited significantly enhanced analgesic activity, with compounds 5a and 5c having ED50 values of 1.2 and 1.6 mg/kg, respectively, indicating higher potency than lappaconitine (3.5 mg/kg). A metabolic analysis of compound 5e was conducted in mice, revealing its primary metabolic processes and metabolites, and providing preliminary exploration for the druggability. Given the multiple analgesic targets of lappaconitine, its analgesic mechanism remains inconclusive. This study, for the first time, analyzed the pharmacological activity characteristics of the lappaconitine analogs using a pharmacophore model and established a three-dimensional quantitative structure-activity relationship (3D-QSAR) to elucidate the quantitative relationship between the structures of the synthesized compounds and their analgesic activities. These findings provide valuable guidance for future structural modification and optimization of analgesic drugs.

Study on the anti-HBV activity of matrine alkaloids from Oxytropis ochrocephala by MTT, 3d-QSAR, molecular docking and molecular dynamics simulation.

To elucidate the structure-activity relationship of 17 matrine alkaloids from Oxytropis ochrocephala Bunge, their effect on hepatitis B surface antigen (HBsAg) secretion was studied using the MTT assay. A 3D-QSAR analysis showed a strong correlation between chemical structures and biological activities (q2 = 0.625, r2 = 0.859). Molecular docking and molecular dynamics simulations revealed that hydrogen bonding and hydrophobic interactions with hepatitis B core protein (PDB:5T2P) are key to inhibiting HBsAg secretion, suggesting potential for developing natural anti-hepatitis B drugs.

Design, Synthesis, Antifungal Evaluation, and Three-Dimensional Quantitative Structure-Activity Relationship of Novel 5-Sulfonyl-1,3,4-thiadiazole Flavonoids.

Plant pathogenic fungi frequently disrupt the normal physiological and biochemical functions of plants, leading to diseases, compromising plant health, and ultimately reducing crop yield. This study aimed to address this challenge by identifying antifungal agents with innovative structures and novel mechanisms of action. We designed and synthesized a series of flavonoid derivatives substituted with 5-sulfonyl-1,3,4-thiadiazole and evaluated their antifungal activity against five phytopathogenic fungi. Most flavonoid derivatives demonstrated excellent antifungal activity against Botrytis cinerea (B. cinerea), Alternaria solani (A. solani), Rhizoctorzia solani (R. solani), Fusarium graminearum (F. graminearum), and Colletotrichum orbiculare (C. orbiculare). Specifically, the EC50 values of 38 target compounds against R. solani were below 4 µg/mL, among which the compounds C13 (EC50 = 0.49 µg/mL), C15 (EC50 = 0.37 µg/mL), and C19 (EC50 = 0.37 µg/mL) had the most prominent antifungal activity, superior to that of the control drug carbendazim (EC50 = 0.52 µg/mL). Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) images of the cellular ultrastructures of R. solani mycelia and cells after treatment with the compound C19 revealed sprawling growth of hyphae, a distorted outline of their cell walls, and reduced mitochondrial numbers. Studying the 3D-QSAR between the molecular structure and antifungal activity of 5-sulfonyl-1,3,4-thiadiazole-substituted flavonoid derivatives could significantly improve conventional drug molecular design pathways and facilitate the development of novel antifungal leads.

Identification of novel PHGDH inhibitors based on computational investigation: an all-in-one combination strategy to develop potential anti-cancer candidates.

Objective: Biological studies have elucidated that phosphoglycerate dehydrogenase (PHGDH) is the rate-limiting enzyme in the serine synthesis pathway in humans that is abnormally expressed in numerous cancers. Inhibition of the PHGDH activity is thought to be an attractive approach for novel anti-cancer therapy. The development of structurally diverse novel PHGDH inhibitors with high efficiency and low toxicity is a promising drug discovery strategy. Methods: A ligand-based 3D-QSAR pharmacophore model was developed using the HypoGen algorithm methodology of Discovery Studio. The selected pharmacophore model was further validated by test set validation, cost analysis, and Fischer randomization validation and was then used as a 3D query to screen compound libraries with various chemical scaffolds. The estimated activity, drug-likeness, molecular docking, growing scaffold, and molecular dynamics simulation processes were applied in combination to reduce the number of virtual hits. Results: The potential candidates against PHGDH were screened based on estimated activity, docking scores, predictive absorption, distribution, metabolism, excretion, and toxicity (ADME/T) properties, and molecular dynamics simulation. Conclusion: Finally, an all-in-one combination was employed successfully to design and develop three potential anti-cancer candidates.

Pharmacophore mapping, 3D QSAR, molecular docking, and ADME prediction studies of novel Benzothiazinone derivatives.

In the quest to combat tuberculosis, DprE1, a challenging target for novel anti-tubercular agents due to its small size and membrane location, has been a focus of research. DprE1 catalyzes the transformation of DPR into Ketoribose DPX, with Benzothiazinone emerging as a potent pharmacophore for inhibiting DprE1. Clinical trial drugs such as BTZ043, BTZ038, PBTZ169, and TMC-207 have shown promising results as DprE1 inhibitors. This study employed pharmacophore mapping of Pyrazolopyridine, Dinitrobenzamide, and Benzothiazinone derivatives to identify crucial features for eliciting a biological response. Benzothiazinone (Ligand code: 73) emerged as a reference ligand with a fitness score of 3.000. ROC analysis validated the pharmacophore with an excellent score of 0.71. To build a 3D QSAR model, a series of Benzothiazinone congeneric derivatives were explored. The model exhibited strong performance, with a standard deviation of 0.1531, a correlation coefficient for the training set (R2) value of 0.9754, and a correlation coefficient for test set Q2 value of 0.7632, indicating robust predictive capabilities. Contour maps guided the design of novel benzothiazinone derivatives, emphasizing steric, electrostatic, hydrophobic, H-bond acceptor, and H-bond donor groups for structure-activity relationships. Docking studies against PDB ID: 4NCR demonstrated favorable scores, with interactions aligning well with the in-built ligand 26 J. Docking validation via RMSD values supported the reliability of the docking results. This comprehensive approach aids in the design of novel benzothiazinone derivatives with potential anti-tubercular properties, contributing to the development of novel anti-tubercular agents which can be pivotal in the eradication of tuberculosis.