BACKGROUND:Histone deacetylase 6 (HDAC6) and heat shock protein 90 (Hsp90) are crucial therapeutic targets in cancer research with their interconnected roles in regulating protein homeostasis and cellular processes. The interaction of these proteins within the cytosolic complex plays a critical role in regulating cancer cell survival and progression. Notably, current studies highlight that the simultaneous inhibition of HDAC6 and Hsp90 can produce synergistic effects and offer a promising therapeutic potential for combating malignant cancers. OBJECTIVE:The objective of this study was to explore potential compounds that can inhibit both HDAC6 and Hsp90 proteins. METHODS:In this study, a number of in-silico computational techniques were employed. A total of 791 molecules, sharing at least 30% similarity with previously identified four HDAC inhibitors, were obtained from the ZINC15 database and subjected to docking on HDAC6 and Hsp90 proteins. The top eight ligands demonstrating the best binding scores against both targets, with panobinostat and ganetespib serving as reference compounds for HDAC6 and Hsp90, respectively, were selected for further analysis. Subsequently, ADME prediction and molecular dynamics simulations were conducted on the selected ligands. RESULTS:A detailed molecular docking, molecular dynamics simulations and ADME studies have revealed that ZINC27653366 exhibited the highest inhibitory potential against both Hsp90 and HDAC6 target proteins, making it the most promising inhibitor. CONCLUSION:In conclusion, although additional in vitro and in vivo studies are required for the validation, in silico evaluation of ZINC27653366 may position it as a promising candidate for the treatment of different types of cancers.
INTRODUCTION:Dysregulated cellular signaling pathways involving protein kinases are critically implicated in cancer development. Consequently, protein kinases have emerged as key targets for novel anticancer therapies. A range of kinase inhibitors, including small molecules and monoclonal antibodies, has been developed. Although early strategies focused on achieving high specificity to minimize adverse effects, resistance to these targeted therapies has limited their effectiveness. As a result, broader-spectrum inhibitors that act on multiple cancer-related kinases are now considered more promising therapeutic options. METHOD:We developed twenty-five new pyrrolopyrimidine derivatives featuring diverse substitution patterns to assess their potential as small-molecule inhibitors of the protein kinases CLK4 and HER2, both of which are significant therapeutic targets in metastatic breast cancer. Pyrrolopyrimidine derivatives were synthesized and purified by column chromatography. Their protein kinase inhibitory activity was evaluated through a radioactive ATP-competition assay. RESULTS:The compounds were obtained through a multi-step synthetic procedure, concluding with substitution reactions. The effects of different substituents on the inhibitory properties of the observed protein kinases are analyzed and discussed. DISCUSSION:Aniline-substituted derivatives exhibited the most potent activities, which were further modulated by N-substituted pyrroles. CONCLUSION:We identified both selective and dual inhibitors of the target kinases, demonstrating activity in the nanomolar range.
OBJECTIVE:Staphylococcus aureus (S. aureus) has been one of the pathogenic bacteria for clinical infections, and there is an urgent need for the development of novel anti-S. aureus drugs. SecA is a conserved and essential protein in bacteria and is considered as an ideal target for development. Current screening of inhibitors against SecA has focused on the ATP-binding structural domain, which increases the risk of drug side effects, so a novel screening strategy based on the non-ATP-binding structural domain was chosen in this paper. METHODS:A three-dimensional structural model of S. aureus SecA1N75 was constructed, and molecular docking was utilized to screen small molecules with strong interactions with the non- ATP binding domains from a compound library, and four candidate compounds were finally targeted. Molecular dynamics simulations of the candidate molecules were performed to evaluate their drug potential. RESULTS:The four candidate compounds formed stable interactions with key residues of the SecA binding pocket. Molecular dynamics simulations further showed that the candidate molecules bound to the receptor in a stable conformation with nM-level inhibition constants, displaying potent SecA inhibitory activity. It lays the foundation of a lead compound for the development of antimicrobial drugs targeting SecA. CONCLUSION:In this thesis, an inhibitor screening strategy based on non-ATP binding structural domains was successfully constructed, which breaks through the limitations of traditional methods to screen candidate molecules with high activity and low risk of potential side effects, and provides an innovative solution to meet the challenge of S. aureus drug resistance.
INTRODUCTION:Glycogen synthase kinase-3β (GSK-3β) is a serine/threonine kinase that is involved in the synthesis of glycogen. Among the inhibitors, thiazolidinediones (TZDs) can specifically bind to GSK-3β. They act non-competitively with ATP, and as a result, they are very specific and have fewer side effects. In this research, new TZDs were designed and synthesized, and then their inhibitory effects on GSK-3β enzyme and tau aggregation were investigated. MATERIALS AND METHODS:The structure of the compounds was confirmed using 1H-NMR, 13CNMR, and LC-MASS. The inhibitory activities of the compounds 5a-p, against GSK-3β were evaluated using Z'-LYTE technique, and the IC50 values were determined. RESULTS:Compound 5l (R1 = Me, R2 = 4-F-benzyl, R3 = butyl) with IC50 of 16.1 μM exhibited the most potent inhibition. Also, the binding with tau protein and their inhibitory effects on the accumulation of recombinant human tau protein (1N4R, htau34) were evaluated using the Surface Plasmon Response (SPR) method. In this study also the impact of TZDs on tau aggregation using the Thioflavin T (ThT) assay was investigated. PC12 cells viability study confirmed the neuroprotective effects of compounds against tau aggregates. MD simulation studies showed the interaction of 5l with the active site of GSK-3β (PDB ID: 2OW3) and also its destructive effect on tau aggregate (PDB ID: 5O3L) was studied. CONCLUSION:Overall, the study identified three promising TZDs with potential as inhibitors of GSK-3β and tau proteins, highlighting compound 5l as particularly effective in stabilizing GSK- 3β and disrupting tau aggregation.
BACKGROUND:Phosphatidylinositol-specific phospholipase C (PI-PLC) enzymes catalyze the conversion of phosphatidylinositol-4,5-bisphosphate into the second messengers diacylglycerol and inositol- 1,4,5-trisphosphate, both of which play crucial roles in regulating biochemical processes. Despite the wellestablished link between elevated PI-PLC activity and pathophysiological conditions, no PI-PLC inhibitors are currently in clinical development. Moreover, existing inhibitors demonstrate only limited potency. OBJECTIVE:Due to the structural similarity with known inhibitors with a myo-inositol backbone, DL-1-Ododecylsulfonyl- myo-inositol-3,5-bisphosphate, designated as acid sphingomyelinase inhibitor, and derivatives thereof should be tested for inhibition of PI-PLC activity. METHODS:The newly synthesized compounds were evaluated for their ability to inhibit PI-PLC activity in porcine platelet lysate and porcine brain homogenate, as well as their inhibitory potency against the recombinant isoenzymes PLCγ1 and PLCγ2. The assay measured the release of diacylglycerol from L-α- phosphatidylinositol using HPLC coupled with MS detection. Furthermore, the specificity of selected compounds was assessed by determining their inhibitory potency against other surface-active enzymes through HPLC-based assays. RESULTS:It was found that DL-1-O-dodecylsulfonyl-myo-inositol-3,5-bisphosphate inhibits PI-PLC activity at micromolar concentrations. However, its maximum achievable inhibitory effect was limited to approximately 70%. Through structural modifications, inhibitors were developed that led to near complete inhibition of PIPLC activity. The study also revealed that the alleged PI-PLC inhibitor U73122, still frequently cited in the literature to demonstrate PI-PLC involvement in biochemical processes, is unsuitable for this purpose. Consistent with observations by others, its inhibitory activity in bionucleophile-containing cell or tissue preparations was found to be significantly lower than its activity against purified PI-PLC enzymes. Additionally, U73122 was shown to inhibit other enzymes, such as cytosolic phospholipase A2α, fatty acid amide hydrolase, and monoacylglycerol lipase, which, like PI-PLC, metabolize lipophilic substrates. In contrast, the newly developed myo-inositol derivatives exhibited reduced sensitivity to bionucleophiles and significantly improved selectivity against the tested surface-active enzymes compared to U73122. CONCLUSION:New compounds exhibiting significant inhibitory activity against PI-PLC have been identified. The findings could prove valuable in the development of clinically applicable PI-PLC inhibitors, particularly for the treatment of cancer. Additionally, the myo-inositol derivatives developed demonstrated greater suitability for studying PI-PLC's role in physiological processes in tissue homogenates compared to the maleimide derivative U73122, which is commonly used for this purpose in scientific research. This advantage arises from the fact that U73122 is a non-specific 'pan-assay interference compound' (PAIN).
BACKGROUND:To date, COVID-19 has caused over 772 million cases, with approximately 7 million deaths, according to the World Health Organization. Therefore, there is a need to develop new drugs to address the challenges posed by this disease. OBJECTIVE:To propose new antiviral agents based on the natural product curcumin as potential protein-protein interaction inhibitors between the SARS-CoV-2 spike receptor binding domain (RBD) and the ACE2 receptor. METHODS:A curcumin-based virtual screening was performed (Tanimoto coefficient= 0.9), and molecular docking analysis were carried out using the RBD as a receptor. Molecular dynamics (MD) using GROMACS were conducted for 120 ns. The SwissADME server was used to predict pharmacokinetics properties. To validate predictions, an in vitro enzyme assay measuring the relative inhibition of the interaction between the RBD and the ACE2 receptor was performed. RESULTS:More than 1300 ligands were evaluated through molecular docking. The docking results were analyzed, and the ligands were classified according to their score and profile of interactions with residues of the RBD of the SARS-CoV-2 S glycoprotein. The top ten with the best scores and interactions were selected to verify the commercial availability. The lead compound Cu-1 demonstrated significant interactions with the RBD and stability in MD simulations, was acquired and evaluated in vitro. Compound Cu-1 inhibited 36 ± 0.7% the interaction between the SARSCoV- 2 spike and the ACE2 receptor. In addition, Cu-1 was shown to have an acceptable druglikeness and pharmacokinetic profile. CONCLUSION:Curcumin provides a scaffold for identifying novel compounds with potential antiviral activity. Further studies on compound Cu-1 could yield on optimizing its structure to increase activity targeting the RBD of the S glycoprotein.
BACKGROUND:Protein Interacting with NIMA1 (PIN1) is a distinct enzyme, known as a peptidyl-prolyl cis-trans isomerase (PPIase), which catalyzes the cis-trans isomerization of amide bonds in proteins containing phosphoserine/threonine-proline (pSer/Thr-Pro) motifs, presenting a unique therapeutic opportunity for addressing multiple disorders. METHODS:A series of 140 thiazole compounds were created using the shape similarity technique with the intention of discovering effective PIN1 inhibitors with a new scaffold. The designed compounds were docked into the enzyme's ATP binding site, and the binding free energies for all docked conformations were calculated. The compounds were evaluated for their ADMET and drug-likeness properties. Following the identification of top candidates, molecular dynamics simulations were conducted to investigate the binding dynamics of the highest-scoring compound. RESULTS:Based on computational findings, sixteen compounds were identified as potential PIN1 inhibitors. Among the sixteen compounds, four (S8Ba, S8Bb, S8Bc, and S8Bd) exhibited the most favorable ADMET profiles and robust interactions with key PIN1 residues. Molecular dynamics simulations confirmed that S8Ba and S8Bc exhibited the most promising activity over 100ns. CONCLUSION:The results corroborated the docking outcomes, validating the selected hits as potential PIN1 inhibitors. This breakthrough could influence the development of therapeutic leads for combating diabetes, cancer, and Alzheimer's disease.
AIMS:A simple and efficient synthesis of 14 new (9a-9n) N-phenacyl-2-pyridones with good yields (up to 75%), is reported. The synthesized derivatives were screened for their in vitro radical scavenging activity against 1,1-diphenyl-2-picrylhydrazyl (DPPH), their in vitro antimicrobial potential was tested against human pathogenic bacterial strains, including Bacillus cereus, Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa, as well as the fungal strain Candida albicans. METHODS:All compounds displayed modest antioxidant activity, with compound 9b being the most potent in the DPPH radical scavenging assay. Most of the synthesized compounds exhibited good to excellent antimicrobial activity, however, the compounds (9d, and 9b) showed maximum inhibition zone diameters of 18.75, and 18.25 mm respectively, demonstrating better antimicrobial potential than the standard drug streptomycin against Staphylococcus aureus. RESULTS:Compound 9f was found most effective against Pseudomonas aeruginosa with a 23.25 mm zone of inhibition against a 17.50 mm zone of inhibition of the standard, streptomycin. Molecular docking of the compounds 9d and 9f with tyrosyl-tRNA synthetase revealed good binding with the target. CONCLUSION:The electron-withdrawing substituents on the aryl ring of synthesized N-phenacyl-2- pyridones improved the antioxidant activity, however, for Gram-positive bacteria, less lipophilic or more hydrophilic substituents, such as halogens, displayed better antimicrobial activity. Similarly, it was the more lipophilic substitutions on the aryl ring that improved the antimicrobial activity against Gram-negative bacteria.
Background: PARP1 (poly ADP-ribose polymerase 1, also known as ADPRT1) plays a significant role in DNA repair and has become an attractive target for treating PARP1-related diseases, such as cancer. Objective: This study aimed to discover inhibitors targeting PARP1 from the phytochemicals of Huangbai (Phellodendron chinense Schneid.), Baixianpi (Dictamnus dasycarpus Turcz.), and Shechuangzi (Cnidium monnieri (L.) Spreng.). Methods: The chemical compositions of Huangbai, Baixianpi, and Shechuangzi were extracted from the HERB database. Next, a combination of molecular docking and PARP1 enzyme assay was used to identify PARP1 inhibitors from these chemical components. Finally, molecular dynamics simulation and binding free energy calculation were used to explore the detailed interaction mode of these inhibitors with PARP1. Results: A total of 507 chemical constituents of Huangbai, Baixianpi, and Shechuangzi were collected from the HERB database. Four potential PARP1 inhibitors were screened based on molecular docking and PARP1 enzyme assay. Demethyleneberberine exhibited strong PARP1 inhibitory activity with an IC50 value of 2.0 ± 0.8 μM. The IC50 values of the inhibitory activities of 8-hydroxy dictanmnine, meranzin hydrate, and osthol on PARP1 ranged from 44 μM to 76 μM. Molecular dynamics simulation and binding free energy calculation suggested that the nonpolar interaction energies of HIS862, GLY863, TYR889, TYR896, PHE897, and TYR907 played a primary role in the binding of inhibitors to PARP1. Conclusion: Integrating molecular simulation and bioactivity testing was found to be an effective approach for the rapid discovery of targeted PARP1 inhibitors. Demethyleneberberine demonstrated strong PRAP1 inhibitory activity and has a good prospect for development.
OBJECTIVE:In the pursuit of identifying divergent scaffolds for potential anticancer and anti-mycobacterial agents, a novel series of Schiff-based threaded 1,2,3-triazoles was designed and synthesized. METHODS:In this study, novel Schiff-based threaded 1,2,3-triazoles have been meticulously crafted and synthesized. Chemical structures of the synthesized molecules were confirmed by 1H NMR, 13C NMR and Mass spectra. Synthetic analogs were further evaluated for their antiproliferative, antitubercular and antimicrobial potentials by in vitro assays. RESULTS:The in vitro anti-tumor (anti-proliferative) evaluation on HT29 cancer cells revealed that compounds 8b and 8h exhibited remarkable inhibitory activity with IC50 values of 25 ± 0.8 and 24 ± 0.9 μM. In the context of anti-mycobacterial analysis, compound 8c demonstrated promising activity (6.25 μM) against Mycobacterium tuberculosis H37Rv. Moreover, compounds 8d and 8e displayed equipotent antimicrobial potential (3.12 μM) comparable to Ciprofloxacin against both Staphylococcus aureus and Escherichia coli. Molecular docking studies unveiled that 8c exhibited robust binding within the active pocket of carbonic anhydrase XII (docking energy -8.4 kcal/mol) and demonstrated a promising docking profile with β-ketoacyl ACP synthase I (docking energy - 9.5 kcal/mol) in the enzyme's binding pocket. CONCLUSION:Structure-activity relationship (SAR) analysis identified three pivotal pharmacophores; 1,2,3-triazole, aromatic ring system (substituted with halogens and -NO2), and imine functionalities as crucial for the development of dual inhibitors targeting cancer and tuberculosis, showcasing an outstanding in silico ADMET profile. Therefore, these compounds merit consideration as noteworthy pharmacological lead molecules in the realm of cancer and tuberculosis drug discovery and development.
INTRODUCTION:Development of theranostics agents targeted towards particular receptors can effectively help in the management of cancer. The overexpression of the sigma-2 receptor (S2R) in tumors establishes it as a prominent biomarker for cancer cells. METHODS:Radiotheranostics rely on the design of specific molecules having versatility in applications of diagnosis and therapy by merely changing the radioisotope. We have designed a novel radiotheranostic S2R-targeted ligand using cyclohexylpiperazine and performed docking studies to narrow down the potential efficacious ligand. The potential molecule with G-score = -7.0 kcal/mol, was then synthesized using a three steps reaction including conjugation of 2-(4- cyclohexylpiperazine-1-yl)ethyl(CYX) with DTPA chelator. Subsequently, the molecule has been radiolabelled with 99mTc using stannous chloride as a reducing agent, and a radiolabellieng efficiency of 95.0 ± 0.59% for 99mTc-CYX-DTPA. As proof of concept, the molecule has been evaluated for its binding affinity and specificity using sigma receptors isolated from the liver membrane homogenates of mice. The binding affinity was found to be Kd = 12.84 ± 0.395 nM; Bmax = 0.5258 ± 0.001 fmol/mg, indicating a high affinity for the receptors. RESULTS:In addition, the molecule was also assessed for biocompatibility using haemolysis analysis and cytotoxicity on HEK cells and MDA-MB-23, wherein the molecule showed no significant cytotoxicity up to 72 h on HEK cells and 32.42% cytotoxicity on MDA-MB-231 cells. CONCLUSION:The future work will concentrate on the demonstration of in vivo targeting and sitespecific accumulation of the molecule along with its suitability for theranostics applications.
BACKGROUND:Acetyl and butyrylcholinesterase are significant enzymes involved in neurological diseases, and the development of more effective inhibitors is crucial for beneficial interference. OBJECTIVE:To evaluate the cholinesterase inhibition effect of the synthetic bis-Schiff base compounds and discover the electronic properties as well as binding affinities through computational studies. METHODS:The compounds were synthesized and screened against acetyl and butyrylcholinesterase inhibitory activities in-vitro, while DFT analysis and molecular docking studies were performed for the product compounds. RESULTS:Seven compounds, including 2a, 2b, 2e, 2c, 2d, 2i, and 2j, exhibited excellent AChE activity, while nine compounds showed potent BChE inhibition compared to galantamine (IC50 = 156.4 ± 1.13 μM). Furthermore, the recent study on molecules 2a-e has provided valuable insights into their mechanism of action as inhibitors of the enzyme ChE, which is crucial for understanding how to regulate this enzyme's activity. Through the use of Time-Dependent Density Functional Theory (TD-DFT), the electronic characteristics of these molecules were meticulously examined, revealing that the Highest Occupied Molecular Orbitals (HOMO) are extensively delocalized across the molecular frameworks of the most active 2a-e compounds. This suggests a significant degree of electron delocalization, which is often associated with chemical reactivity and stability. In comparison to standard galantamine, these compounds demonstrate a lower electrophilicity index, which is indicative of their increased biological efficacy and lower toxicity. CONCLUSION:These derivatives showed excellent AChE and BChE activities with favorable electronic properties and superior binding affinities, highlighting their potential as effective inhibitors as therapeutic agents.
BACKGROUND:The advent of Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of the Coronavirus Disease 2019 (COVID-19) pandemic, has impacted physical and mental health worldwide. The lack of effective antiviral drugs necessitates a robust therapeutic approach to develop anti-SARS-CoV-2 drugs. Various investigations have recognized ACE2 as the primary receptor of SARS-CoV-2, and this amalgamation of ACE2 with the spike protein of the coronavirus is paramount for viral entry into the host cells and inducing infection. Consequently, restricting the virus's accessibility to ACE2 offers an alternative therapeutic approach to averting this illness. OBJECTIVE:The study aimed to identify potent inhibitors with enhanced affinity for the ACE2 protein and validate their stability and efficacy against established inhibitors via molecular docking, machine learning, and MD simulations. METHODOLOGY:202 ACE2 inhibitors (PDB ID and 6LZG), comprising repurposed antiviral compounds and specific ACE2 inhibitors, were selected for molecular docking. The two most effective compounds obtained from docking were further analyzed using machine learning to identify potential compounds with enhanced ACE2-binding affinity. To refine the dataset, molecular decoys were generated through the Database of Useful Decoys: Enhanced (DUD-E) server, and Singular Value Decomposition (SVD) was applied for data preprocessing. The Tree-based Pipeline Optimization Tool (TPOT) was then utilized to optimize the machine learning pipeline. The most promising ML-predicted compounds were re-evaluated through docking and subjected to Molecular Dynamics (MD) simulations to evaluate their structural stability and interactions with ACE2. Finally, these compounds were evaluated against the top two pre-established inhibitors using various computational tools. RESULTS:The two best pre-established inhibitors were identified as Birinapant and Elbasvir, while the best machine-learning-predicted compounds were PubChem ID: 23658468 and PubChem ID: 117637105. Pharmacophore studies were conducted on the most effective machine-learning-predicted compounds, followed by a comparative ADME/T analysis between the best ML-screened and pre-established inhibitors. The results indicated that the top ML compound (PubChem ID: 23658468) demonstrated favorable BBB permeability and a high HIA index, highlighting its potential for therapeutic applications. The ML-screened ligand demonstrated structural stability with an RMSD (0.24 nm) and greater global stability (Rg: 2.08 nm) than Birinapant. Hydrogen bonding interactions further validated their strong binding affinity. MM/PBSA analysis confirmed the ML-screened compound's stronger binding affinity, with a binding free energy of - 132.90 kcal/mol, indicating enhanced stability in complex formation. CONCLUSION:The results emphasize the efficacy of integrating molecular docking, machine learning, and molecular dynamics simulations in facilitating the rapid identification of novel inhibitors. PubChem ID: 23658468 demonstrates robust binding affinity to ACE2 and favorable pharmacokinetic properties, establishing it as a promising candidate for further investigation.
INTRODUCTION:Tyrosinase, a key enzyme in melanin biosynthesis and food browning, has become an important target for inhibitor development. This study aimed to investigate the inhibitory potential of 4,6-dihydroxyaurone derivatives with varied ring B substituents on mushroom tyrosinase. METHODS:A set of 4,6-dihydroxyaurone derivatives, each with varied substituent patterns on ring B, were designed and subjected to computational studies to predict their binding affinity, binding modes with tyrosinase, and drug-likeness properties. These aurone derivatives were subsequently synthesized and evaluated in vitro for their tyrosinase inhibitory activity. Enzyme kinetics studies were conducted to determine the mode of tyrosinase inhibition. RESULTS:Computational studies of the twenty designed aurone derivatives indicated their strong binding within the active site and exhibited favorable drug-likeness properties. In vitro UV-Vis spectrophotometric assays of the synthesized compounds revealed that compound 5h, featuring a 3,4-dichlorophenyl substituent on ring B, showed the most potent tyrosinase inhibitory activity (IC50 = 6.3 ± 0.3 μM) compared to kojic acid (IC50 = 136.5 ± 11.5 μM). Kinetic studies and molecular docking simulations indicated that compound 5h inhibits tyrosinase through a mixedtype inhibition mechanism, with competitive and uncompetitive inhibition constants of 21 μM and 68 μM, respectively. CONCLUSION:These findings highlight the promising potential of 4,6-dihydroxyaurone derivatives as potent tyrosinase inhibitors for applications in pharmaceuticals, cosmetics, and agriculture.
BACKGROUND AND OBJECTIVES:Cabozantinib, a Tyrosine Kinase Inhibitor (TKI), is widely used in Renal Cell Carcinoma (RCC) therapy but often causes serious side effects such as myelosuppression, immunosuppression, and angiopathy. This study aims to identify key protein targets responsible for the therapeutic efficacy and adverse reactions of cabozantinib and to explore structural modifications to reduce toxicity while preserving efficacy. METHODS:A non-randomized computational approach was employed, screening 400 potential protein targets using SwissTargetPrediction and ChemBL databases. Molecular docking and Structure-Activity Relationship (SAR) analysis were performed to assess interactions between cabozantinib and identified targets, focusing on structural elements contributing to toxicity. RESULTS:Three primary proteins were identified as responsible for the anti-tumor effects of cabozantinib, while three others were linked to its side effects. Docking analysis revealed that the methoxyphenyl group in cabozantinib formed undesirable hydrogen bonds with toxicity-related proteins. Modulating these off-target interactions by minimizing hydrogen bonding in this region could significantly reduce adverse effects. CONCLUSION:These findings provide structural insights into cabozantinib's dual effects and suggest optimization strategies for TKI design, offering a pathway toward safer and more effective RCC treatments.
INTRODUCTION:SYK (Spleen Tyrosine Kinase) regulates immune response and is a promising target for cancer, sepsis, and allergy therapies. This study aims to create novel compounds that serve as alternative inhibitors for cancer treatments targeting SYK. METHODS:A thorough combination of machine learning (ML) and physics-based methods was employed to achieve these goals, encompassing de novo design, multitier molecular docking, absolute binding affinity computation, and molecular dynamics (MD) simulation. RESULTS:A total of 5576 novel molecules with key pharmacophoric features were generated using an ML-driven de novo approach against 21 diaminopyrimidine carboxamide analogs. Pharmacokinetic and toxicity evaluation assisted by the ML approach revealed that 4353 chemical entities fulfilled the acceptable pharmacokinetic and toxicity profiles. By screening through binding energy threshold from the physics-based multitier molecular docking, and ML-assisted absolute binding affinity identified the top four molecules such as RI809 (2-([1,1'-biphenyl]-3-ylmethyl)-4-((2- aminocyclohexyl)oxy)benzamide), RI1393 (4-((2-aminocyclohexyl)amino)-2-(3-(1-methyl-1Hpyrazol- 5-yl)-4-(trifluoromethyl)benzyl)benzamide), RI2765 (2-([1,1'-biphenyl]-3-ylmethyl)-4-((4- aminocyclohexyl)methyl)benzamide), and RI3543 (2-([1,1'-biphenyl]-2-ylmethyl)-4-(piperidin-3- yloxy)benzamide). The final molecules identified exhibit a strong affinity for SYK, attributed to their structural diversity and notable pharmacophoric characteristics. All-atom MD simulations showed that each final molecule retained significant binding interactions with SYK and stability in dynamic states, indicating their potential as anticancer agents. Calculated binding free energy for selected molecules using molecular mechanics with generalized Born and surface area (MMGBSA) ranged from -6 to -35 kcal/mol, indicating strong SYK affinity. CONCLUSION:In conclusion, the integration of AI and physics-based methods successfully developed promising SYK inhibitors with significant potential. The molecules reported could be vital anticancer agents subjected to experimental validation.
BACKGROUND:This work presents the synthesis of Ru(II)NHC complexes bearing a series of 4-fluorobenzyl group. These complexes have been characterized by a variety of spectroscopic methods (1H NMR, 13C NMR, and FTIR) and by elemental analysis techniques. METHODS:These complexes' antitumor activities against SH-SY5Y (human neuroblastoma) and HCT116 (human colon cancer) were investigated by 3-(4,5-dimethylthiazole-2-yl)-2,5-biphenyl tetrazolium bromide (MTT) assay. RESULTS:The results showed that all the synthesized complexes exhibited significant cytotoxic effect with low IC50 values 15 ± 0.57, 15.26 ± 0.71, 7.64 ± 0.30, 27.66 ± 0.36 and 14.45 ± 0.84 (μg/mL) respectively. CONCLUSION:Furthermore, apoptosis assessed by double labeling with Annexin V-FITC/PI indicated that complexes 1b and 1d can effectively induce apoptosis and inhibit cell proliferation at the S phase in SH-SY5Y cells. Taken together, Ru(II)NHC complexes containing the 4- fluorobenzyl group have significant potential for the development of novel, highly effective anticancer agents.
INTRODUCTION:Liver cancer is considered one of the most common types of cancer and a major cause of ephemerality worldwide having a higher prevalence rate in Asia and sub-Saharan Africa. The alpha-fetoprotein (AFP) is a serum glycoprotein that belongs to a class of oncodevelopmental proteins and is also involved in tumor formation. METHODS:In the current effort, a hybrid approach of virtual screening followed by pharmacophore generation and molecular dynamic simulation analyses were performed. The screened top-ranked 10 docked compounds from the selected anti-cancer compound library were utilized to generate the ligand-based pharmacophore. Virtual screening was performed two-dimensional similarity search against the selected natural compound library based on their physicochemical properties. It was observed that all the compounds from the anti-cancer compound library and natural compound library showed similar binding resides. RESULTS:Therefore, the top-ranked screened compounds that showed the least binding energy and highest binding affinity against AFP, obtained through the anti-cancer drug library and natural compound library were reported. The molecular docking analyses revealed that Leu-219, His-222, Lys-242, Lys-246, His-316, Glu-318, Ala-366, Val-367, Gly-475, Ile-479, Ala-471, Asp-478 were observed as potential residues for interaction. CONCLUSION:The observed results of virtual screening, molecular docking, and MD simulation analyses entail noteworthy observations illustrating that NC002 was a potent inhibitor. The proposed compound NC002 may have potential against liver cancer by targeting AFP based on MD simulation analyses, PCA, and MM-GBSA.
Introduction: Casein Kinase 2 (CK2), discovered as one of the earliest protein kinases, is a ubiquitous Ser/Thr protein kinase-specific to acidic environments. CK2 has been implicated in regulating diverse cellular processes and has been linked to the onset of various diseases, including cancer. Method: Consequently, modulating CK2 function has emerged as a potential therapeutic strategy. However, currently, available CK2 inhibitors or modulators often lack sufficient specificity and potency Results: The results were validated through QSAR of curcumin derivatives, Pharmacophore modeling, virtual screening performed for filtered curcumin-like featured derivatives from the database, and Molecular Docking approaches. Since there is a solved crystal structure of high-resolution Xray crystal structures of Human protein kinase CK2 alpha in complex with ferulic aldehyde.Results: The results were validated through QSAR of curcumin derivatives, Pharmacophore modeling, virtual screening performed for filtered curcumin-like featured derivatives from the database, and Molecular Docking approaches. Since there is a solved crystal structure of high-resolution Xray crystal structures of Human protein kinase CK2 alpha in complex with ferulic aldehyde. Conclusion: Also, structure-based virtual screening was performed against a total of 3253 compounds from different libraries, and only the top 4 best-hit compounds with exceptional docking scores exceeding >-7 kcal/mol (more than 7 kcal/mol) were screened and analyzed. However, to validate their therapeutic potential, these compounds require in-vitro evaluation to assess their CK2 targeting ability
Background: Myrica esculenta (Myricaceae) are common in the Indian Himalayas. Traditional medicine uses it to treat chronic bronchitis, inflammation, stomach ulcers, anaemia, diarrhoea, asthma, and ear, throat, and nose disorders. Its varied medicinal benefits are recognised in the ayurvedic pharmacopoeia. Aim: Isolation of Bioactive Compounds from M. esculenta: Assessment of Antioxidant Activity and Molecular Docking Studies Targeting the H+K+-ATPase enzyme and H2 Receptor Material and Methods: The fruit of the Myrica esculenta plant was extracted. The total phenolic and total flavonoid content of the extract were determined. Following column chromatography, two phytoconstituents were identified by mass spectroscopy, FTIR, and NMR. The antioxidant activity of phytoconstituents was evaluated using the DPPH Scavenging Assay, Reactive Nitrogen Oxide Scavenging Assay, and Hydroxyl Free Radical Scavenging Assay. Then, molecular docking studies were performed against the H+K+-ATPase enzyme and H2 Receptor. Results: The research successfully extracted methanolic extract from M. esculenta by maceration, which yielded rich in flavonoids and phenolic content and isolated compounds using column chromatography, which was further characterized to be myricetin and catechin using Mass spectroscopy, FTIR, and NMR. The further evaluation of the antioxidant activity of compounds demonstrated significant activity with IC50 value indicating strong free radical scavenging activity. Molecular docking studies were performed against the H+K+-ATPase enzyme and H2 Receptor, revealing that both the compounds exhibit high binding affinity and favorable interactions with key sites. Conclusion: The findings suggest that the isolated compounds myricetin and catechin possess potential antioxidant activity and could be a potential therapeutic target for the H+K+-ATPase enzyme and H2 Receptor.
