Drug-likeness Score Research Articles

Fragment and torsion biasing algorithms for construction of small organic molecules in proteins using DOCK.

The computational construction of small organic molecules (de novo design), directly in a protein binding site, is an effective means for generating novel ligands tailored to fit the pocket environment. In this work, we present two new methods, which aim to improve de novo design outcomes using (1) biasing algorithms to prioritize selection and/or acceptance of fragments and torsions during growth, and (2) parallel-based clustering and pruning algorithms to remove duplicate molecules as candidate fragment are added. Large-scale testing encompassing thousands of simulations were employed to interrogate the methods in terms of multiple metrics which include numbers of duplicate molecules generated, pairwise-similarity, focused library reconstruction rates, fragment and torsion frequencies, fragment and torsion rank scores, interaction energy and drug-likeness scores, and 3D pose comparisons. The biasing algorithms, particularly those that include fragment and torsion components simultaneously, led to molecules that more closely mimicked the distributions of fragments and torsions found in drug-like libraries. The new parallel-based clustering and pruning algorithms, compared with the existing serial approach, also led to larger ensembles comprised of topologically unique molecules with much greater efficiency by removing redundant growth paths.

Emodin derivatives as novel potent DPP-4 inhibitors: Design, synthesis, and in vitro evaluation

Dipeptidyl peptidase-4 (DPP-4) inhibitors have gained recognition as effective agents for lowering blood sugar levels, significantly improving glycemic control for individuals with type 2 diabetes mellitus (T2DM). Emodin, an anthraquinone derived from the traditional herbs rhubarb (Rheum officinale) and Polygonum cuspidatum, has been identified as an important component in the development of new treatments for diabetes. In the present work, we explored the DPP-4 inhibitory activity of emodin derivatives. This study focused on the design, synthesis, and evaluation of emodin derivatives for their in vitro DPP-4 inhibitory activity. Molecular docking studies indicated that 3-o-toluoyl emodin (OTEM) had the lowest docking score (−134.073) against the DPP-4 protein among the tested compounds. OTEM also achieved the highest drug-likeness score of 0.56 and demonstrated DPP-4 inhibitory activity, with an IC50 value of 0.77 μM. Furthermore, structure-activity relationship (SAR) analysis suggested that the addition of an ortho-toluoyl group at the C-3 position could enhance DPP-4 inhibition. Additionally, quantitative structure-activity relationship (QSAR) model assessments revealed that log P was the only descriptor significantly influencing DPP-4 inhibitory activity. Therefore, the current study indicates that OTEM could serve as a promising lead compound to address the demand for antidiabetic agents.

Synthesis, characterization, and in vitro-in ovo toxicological screening of silibinin fatty acids conjugates as prodrugs with potential biomedical applications.

Silibinin (SIL), the most active phytocompound from Silybum marianum (L.), exerts many biological effects but has low stability and bioavailability. To overcome these drawbacks, the current research proposed the synthesis of silibilin oleate (SIL-O) and silibilin linoleate (SIL-L) derivatives as prodrugs with potentially optimized properties for biomedical applications, and the establishment of their in vitro-in ovo safety profiles. The physicochemical characterization of the obtained compounds using density functional theory (DFT) calculations, and Raman and 1H liquid-state nuclear magnetic resonance (NMR) spectroscopy confirmed the formation of SIL-O and SIL-L complexes. Computational predictions revealed that these lipophilic derivatives present a lower drug-likeness score (-29.96 for SIL-O and -23.55 for SIL-L) compared to SIL, but an overall positive drug score (0.07) and no risk for severe adverse effects. SIL-O and SIL-L showed no cytotoxicity or impairment in cell migration at low concentrations, but at the highest concentration (100 μM), they displayed distinct toxicological profiles. SIL-L was more cytotoxic (on cardiomyoblasts - H9c2(2-1), hepatocytes - HepaRG, and keratinocytes - HaCaT) than SIL-O or SIL, significantly inhibiting cell viability (<60%), altering cellular morphology, reducing cell confluence (<70%), and inducing prominent apoptotic-like nuclear features. At the concentration of 100 μM, SIL-O presented an irritation score (IS) of 0.61, indicating a lack of irritant effect on the chorioallantoic membrane (CAM), while SIL-L was classified as a slight irritant with an IS of 1.99. These findings outline a more favorable in vitro and in ovo biocompatibility for SIL-O compared to SIL L, whose applications are dosage limited due to potential toxicity.

Cytotoxicity, Proapoptotic Activity and Drug-like Potential of Quercetin and Kaempferol in Glioblastoma Cells: Preclinical Insights

Despite the increasing understanding of the pathogenesis of glioblastoma (GBM), treatment options for this tumor remain limited. Recently, the therapeutic potential of natural compounds has attracted great interest. Thus, dietary flavonoids quercetin (QCT) and kaempferol (KMF) were investigated as potential cytostatic agents in GBM. Moreover, the physicochemical properties of QCT and KMF, determining their bioavailability and therapeutic efficiency, were evaluated. We proved that both polyphenols significantly reduced the viability of GBM cells. We also demonstrated that both QCT and KMF evoked the cytotoxic effect in T98G cells via induction of apoptotic cell death as shown by increased activity of caspase 3/7 and caspase 9 together with an overexpression of the cleaved form of PARP. Apoptosis was additionally accompanied by the activation of stress responses in QCT- and KMF-treated cells. Both polyphenols caused oxidative stress and endoplasmic reticulum (ER) stress, as demonstrated by the increased generation of reactive oxygen species (ROS), deregulated expressions of superoxide dismutases (SOD2 and Sod1 on protein and transcriptomic levels, respectively), as well as an overexpression of ERO1α, GRP78, p-JNK, and an up-regulation of Chop, Atf4 and Atf6α genes. The antitumor effect of QCT and KMF was also confirmed in vivo, showing reduced growth of tumor xenografts in the chick chorioallantoic membrane (CAM) experiment. Moreover, electrophoretic light scattering (ELS) was used to measure the zeta potential of cell membranes upon exposition to QCT and KMF. Additionally, on the basis of existing physicochemical data, the drug-likeness score of QCT and KMF was evaluated. Analyses showed that both compounds accomplish Lipinski’s Rule of 5, and they both fit into the criteria of good central nervous system (CNS) drugs. Altogether, our data support the idea that QCT and KMF might be plausible candidates for evaluation as therapeutic agents in preclinical models of glioblastoma.

Investigation of cytotoxic indoleninyl-thiobarbiturate zwitterions as DNA targeting agents

A series of indoleninyl-thiobarbiturate zwitterions were synthesized in up to 83 % yields from the Knoevenagel condensation between N-substituted diformyl indolenine and thiobarbiturate. The structures were characterized by spectroscopic methods such as NMR (1H, 13C), FT-IR, high-resolution mass spectrometry (HR-MS) and elemental analysis. However, their physicochemical properties and biological activities remain elusive. Herein, results from in silico ADMET calculations and cytotoxicity predictions suggest that all zwitterions are likely to exhibit a higher bioavailability and more specific cytotoxicity than doxorubicin. The notably high predicted cytotoxicity of 2d and drug-likeness score of 2f may be linked to the position of the fused benzene ring and methoxy groups, respectively. The initial biological assessment of these compounds began with in vitro DNA-binding studies because the treatment of numerous diseases such as cancer and bacterial infections is linked to DNA interactions. Zwitterion 2f demonstrated the most significant spectral change in DNA binding studies, suggesting a possible role of the methoxy group in inducing DNA binding activity. The hypothesis that 2f interacts with DNA through groove binding was confirmed by observations made during salt-back titration and DNA denaturation experiments. It was anticipated that the non-zwitterionic 2f would interact more stably with DNA (PDB code: 453D) at the minor groove than its zwitterionic form based on molecular docking calculations and molecular dynamic (MD) simulations. Additionally, the MTT assay demonstrates that 2f is moderately cytotoxic to the human breast cancer cell line MDA-MD-231, most probably as a result of the previously stated DNA binding mechanisms. Overall, the computational and in vitro data suggest the potential application of 2f as a cytotoxic DNA-targeting agent.

Synthesis, Molecular Docking Studies and Biological Evaluation of N-(α-Benzamido Cinnamoyl) Piperonal Hydrazones

Background: Nowadays, inflammation is recognized as the underlying cause of a number of diseases, but NSAIDs are the first drug of choice, having several side effects. Additionally, excessive cellular oxidative stress is often considered a major contributor to pathophysiological conditions, the development of cancer, and other diseases. Antimicrobial resistance is a global concern, hence, there is a critical need for the development of novel therapeutic agents to fight the emergence and increasing prevalence of resistant pathogens. This creates an initiation to introduce new molecules which act as efficient therapeutic agents with diminished side effects. Objective: As a part of our search for newer agents with enhanced activity profiles, it was planned to synthesize novel 2- (benzamido)-N-((benzo[d][1,3]dioxol-4-yl)methylene)-3-(substituted phenyl) acrylohydrazides and to investigate them for antiinflammatory, antioxidant, cytotoxic, antimicrobial activities. Furthermore, in silico studies were performed for title compounds to predict molecular properties, bioavailability, drug-likeness, and bioactivity scores, molecular docking studies were also performed against biological targets. Methods: The title compounds 1-14 were synthesized by nucleophilic addition of piperonal in ethanol, few drops of acetic acid to the intermediate 2-(benzamido)-3-(aryl)acrylohydrazides. The title compounds were tested for their antiinflammatory activity by in vivo carrageenan-induced rat paw edema method, in vitro COX-2 inhibition assay; in vitro cytotoxic activity evaluation by MTT assay; antioxidant activity by Lipid peroxidation, DPPH assay, Nitric Oxide scavenging assay and Hydrogen peroxide scavenging assay; and antimicrobial activity by cup plate method. Physicochemical properties and bioactive scores of title compounds were evaluated by in silico studies. Molecular docking studies were carried out for the title compounds against COX-2 (PDB: 5F19) and EGFR (PDB:1XKK). Results: Among the series, 4-Hydroxy-3,5-dimethoxy derivative (5) displayed good anti-inflammatory and antioxidant activities; Vanillinyl derivative (4) displayed good cytotoxicity and antimicrobial activity when compared to that of the respective standards. Compounds 5 &amp; 4 also exhibited good docking scores with COX-2 and EGFR, respectively. All title compounds obeyed Lipinski’s rule of five and also exhibited acceptable molecular properties, drug-likeness properties, and moderate to good bioactivity scores in in silico studies. Conclusion: The study suggested that the title compounds showed notable pharmacological properties, could emerge as lead compounds, and be further explored as promising therapeutic agents.

Spectroscopic investigation of drug potential towards neuronal firing and analysis of molecular docking on (N-(diaminomethylidene)-2-(2,6-dichlorophenyl) acetamide) using DFT theoretical data evidence

Guanfacine is an alpha-A2 adrenergic receptor agonist used for the treatment of attention deficit hyperactivity disorder. Guanfacine also known as (N-(diaminomethylidene)-2-(2,6-dichlorophenyl) acetamide) and in this work it was investigated by interpreting physico-chemical, structural and biological properties using FT-Raman, FT-IR, NMR and UV–Visible spectral datum along with computational results. The optimized geometry of the molecular structure was sketched and deviation of parametric values has been interpreted. The vibrational analysis along with vibrational assignments was carried out to understand the impact of nitro, methylidine, chloro effects on acetamide base molecule to change in drug mechanism. The molecular charge population delocalization on par with substituent was analyzed and purpose of electron cloud accumulation on different entities was justified. The drug likeness score was calculated and bioavailability was tested. The enzymatic target investigation was made on theoretical results of HyperChem. The vibrational characteristics of the compound were evaluated and the chemical-patrician energy of bonds and their influences on drug property change were tested. Chemical reaction path mechanism was mapped to find the root cause of chemical kinetics to enable antimicrobial activity on the heart of Guanfacine molecule. The doubly degenerate interaction orbitals were viewed and the transitions assigned to facilitate the drug activity were studied. The toxicity profile was evaluated by opting enantiomer and validated by simulating VCD spectrograph. The Guanfacine docked into the active site of 5R7Y and 6MOJ indicates conceal antiviral activity, consistent with results from the PASS database. Using the autodock program, docking molecules (ligand-proteins) were simulated.

Exploring novel Apalutamide analogues as potential therapeutics for prostate cancer: design, molecular docking investigations and molecular dynamics simulation.

Introduction: Prostate cancer (PC) ranks as the second most frequent type of cancer in men and is the fourth largest cause of mortality worldwide. Androgenic hormones such as testosterone and dihydrotestosterone are crucial for the development and progression of the prostate gland. Androgenic hormones bind to androgen receptors (AR) and trigger the synthesis of many genes that stimulate the growth of prostate cells, initiating PC growth. Apalutamide (APL) is a non-steroidal antiandrogen drug used to treat PC; however, it also causes a variety of toxicities and resistance during the treatment. Methods: The purpose of this study was to computationally identify new and safer analogues of APL, focusing on improved pharmacokinetic properties and reduced toxicity. Drug likeness (DL) and drug score (DS) were also calculated. Docking studies on the designed analogues were conducted to predict their binding affinities and compare their orientations with the ligands in the original crystal structure. Molecular dynamics (MD) simulation of docked ligands was done using Schrödinger suite. Results: We generated a total of 1,415 analogues for different groups of APL using the bioisosteric approach. We selected 80 bioisosteres based on pharmacokinetic profiles, DL and DS score predictions, and found that the designed APL bioisosteres were optimal to good compared to APL. Analogues APL19, APL35, APL43, APL76, and APL80, formed hydrogen bonds with protein (PDB ID: 5T8E) which is similar hydrogen bonding to the standard (APL). The MD simulation result confirmed that APL43 and APL80 complexes were stable during the 100nS run. Discussion: The results suggest that the APL analogues, particularly APL43 and APL80, are predicted to be potential antiandrogen drugs for the treatment of prostate cancer.

Cholesterol-based mesogenic Schiff’s base derivatives: Biological evaluation, photoluminescence and DFT studies

This study presents the synthesis and comprehensive characterization of novel thiazole Schiff’s base compound linked to various substituted formylphenyl cholesteryl carbonates. The structures were confirmed by elemental analysis and 1H NMR, 13C NMR, and FT-IR spectroscopy. Optical texture investigations revealed that only compound 7a exhibited liquid crystalline behaviour, specifically showing a chiral nematic (N*) mesophase. Thermal properties were analyzed using differential scanning calorimetry (DSC) showing phase transitions, and thermogravimetric analysis (TGA) indicating their stability ranging from 223 to 361 °C. The compound 7a exhibited significant antibacterial activity with zone of inhibition of 18 mm for Staphylococcus aureus (gram-positive) and 25.5 mm for Escherichia coli (gram-negative), and compound 7a and 8 displayed highest antifungal activity with zone of inhibition of 17.5 mm and 24.5 mm against Aspergillus niger and Candida albicans, respectively. Antioxidant activity was assessed using the DPPH assay, where compound 8 showed superior scavenging activity with IC50 value of 101.32 µg/mL. Additionally, the compounds were UV-active and exhibited photoluminescence, showing emission peaks ranging from 412 to 434 nm and a quantum yield of 0.11 to 0.23. In silico predictions indicated promising drug-likeness and bioactivity scores. Density Functional Theory (DFT) calculations provided insights into the electronic properties and molecular interactions. This research highlights the potential of these thiazole Schiff base derivatives for applications in pharmaceuticals and materials science, contributing valuable data on their multifunctional properties.

Virtual screening, molecular docking, MD simulation studies, DFT calculations, ADMET, and drug likeness of Diaza-adamantane as potential MAPKERK inhibitors.

Introduction: Multiple sclerosis (MS) is an autoimmune and inflammatory disease that destroys the protective coating of central nervous system (CNS) nerve fibers and affects over 2.8 million people worldwide. Despite several studies on new therapeutic targets and lead compounds, MS disease has limited treatment options. This condition may be caused by a complicated interaction of environmental and genetic variables. Studies showed that MS-associated microglial cells' increased MAPKERK activity may cause CNS inflammation and oligodendrocyte damage. Thus, screening for lead compounds that inhibit MAPKERK may protect brain cells and slow disease progression. Methods: The study aims to discover compounds that may inhibit MAPKERK as a novel approach for protecting the nervous system in managing MS. The study includes in silico methods, such as virtual screening, molecular docking, Density-functional theory (DFT) investigations (using the B3LYP/6-31++G(d,p) basis set in a gas phase environment), drug likeness scores, and molecular dynamic (MD) simulations. Results and Discussion:During the docking process with the MAPKERK protein, it was shown that the ligand L12 receptor had the best binding affinity, with a docking score of -6.18kcal/mol. To investigate the stability of the binding, a 100ns MD simulation was performed on the complex formed by the MAPKERK protein and L12. The receptor-ligand combination exhibited significant stability throughout the duration of the MD simulation. Additionally, the pharmacokinetic and drug-likeness properties of these ligands suggest that they have the potential to be considered viable candidates for future development in MS management.

Integrating network pharmacology and computational biology to propose Yiqi Sanjie formula's mechanisms in treating NSCLC: molecular docking, ADMET, and molecular dynamics simulation.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related deaths globally. Current treatments often do not fully meet efficacy and quality of life expectations. Traditional Chinese medicine (TCM), particularly the Yiqi Sanjie formula, shows promise but lacks clear mechanistic understanding. This study addresses this gap by investigating the therapeutic effects and underlying mechanisms of Yiqi Sanjie formula in NSCLC. We utilized network pharmacology to identify potential NSCLC drug targets of the Yiqi Sanjie formula via the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. Compounds with favorable oral bioavailability and drug-likeness scores were selected. Molecular docking was conducted using AutoDock Vina with structural data from the Protein Data Bank and PubChem. Molecular dynamics (MD) simulations were performed with Desmond Molecular Dynamics System, analyzing interactions up to 500 nanoseconds using the OPLS4 force field. ADMET predictions were executed using SwissADME and ADMETlab 2.0, assessing pharmacokinetic properties. Using network pharmacology tools, we performed Search Tool for the Retrieval of Interaction Genes/Proteins (STRING) analysis for protein-protein interaction, Kyoto Encyclopedia of Genes and Genomes (KEGG) for pathway enrichment, and gene ontology (GO) for functional enrichment, identifying crucial signaling pathways and biological processes influenced by the hit compounds bifendate, xambioona, and hederagenin. STRING analysis indicated substantial connectivity among the targets, suggesting significant interactions within the cell cycle regulation and growth factor signaling pathways as outlined in our KEGG results. The GO analysis highlighted their involvement in critical biological processes such as cell cycle control, apoptosis, and drug response. Molecular docking simulations quantified the binding efficiencies of the identified compounds with their targets-CCND1, CDK4, and EGFR-selected based on high docking scores that suggest strong potential interactions crucial for NSCLC inhibition. Subsequent MD simulations validated the stability of these complexes, supporting their potential as therapeutic interventions. Additionally, the novel identification of ADH1B as a target underscores its prospective significance in NSCLC therapy, further expanded by our comprehensive bioinformatics approach. Our research demonstrates the potential of integrating network pharmacology and computational biology to elucidate the mechanisms of the Yiqi Sanjie formula in NSCLC treatment. The identified compounds could lead to novel targeted therapies, especially for patients with overexpressed targets. The discovery of ADH1B as a therapeutic target adds a new dimension to NSCLC treatment strategies. Further studies, both in vitro and in vivo, are needed to confirm these computational findings and advance these compounds towards clinical trials.

From petals to healing: consolidated network pharmacology and molecular docking investigations of the mechanisms underpinning Rhododendron arboreum flower's anti-NAFLD effects.

Rhododendron arboreum: Sm., also known as Burans is traditionally used as an anti-inflammatory, anti-diabetic, hepatoprotective, adaptogenic, and anti-oxidative agent. It has been used since ancient times in Indian traditional medicine for various liver disorders. However, the exact mechanism behind its activity against NAFLD is not known. The aim of the present study is to investigate the molecular mechanism of Rhododendron arboreum flower (RAF) in the treatment of NAFLD using network pharmacology and molecular docking methods. Bioactives were also predicted for their drug-likeness score, probable side effects and ADMET profile. Protein-protein interaction (PPI) data was obtained using the STRING platform. For the visualisation of GO analysis, a bioinformatics server was employed. Through molecular docking, the binding affinity between potential targets and active compounds were assessed. A total of five active compounds of RAF and 30 target proteins were selected. The targets with higher degrees were identified through the PPI network. GO analysis indicated that the NAFLD treatment with RAF primarily entails a response to the fatty acid biosynthetic process, lipid metabolic process, regulation of cell death, regulation of stress response, and cellular response to a chemical stimulus. Molecular docking and molecular dynamic simulation exhibited that rutin has best binding affinity among active compounds and selected targets as indicated by the binding energy, RMSD, and RMSF data. The findings comprehensively elucidated toxicity data, potential targets of bioactives and molecular mechanisms of RAF against NAFLD, providing a promising novel strategy for future research on NAFLD treatment.

In vitro anti-microbial, DNA-binding, In silico pharmacokinetics and molecular docking studies of Schiff-based Cu(II), Zn(II) and Pd(II) complexes

Synthesis of salen type Schiff base ligand by the condensation of butane 1,4-diamine with 5-bromosalicyaldehyde has been done. Further, three new mononuclear Schiff based complexes of Cu(II), Zn(II) and Pd(II) have been prepared by the reaction of the Schiff base ligand with appropriate metal salts. The developed Schiff base ligand and metal complexes of Cu(II), Zn(II) and Pd(II) have been well characterized by various spectroscopic techniques like UV–Vis, FT-IR, 1H-NMR, 13C-NMR, EPR, Mass and powder XRD. All the synthesized Schiff base compounds have been tested for antibacterial, antifungal, hemolysis assay and DNA binding activities. The zone inhibition measurements revealed the supremacy and enhanced efficiency of metal complexes as compared to free ligand. The molecular modelling studies were carried to analyze the bonding affinity and inhibition probability of the synthesized complexes with the S. aureus nucleoside diphosphate kinase receptor. The in-silico pharmacokinetics studies such as Lipinski's rule, Veber's rule, drug-likeness score and physiochemical parameters analysis predicted the drug-likeness of the synthesized compounds.

In Silico Repurposing of a Novel Inhibitor (drug) of EGFR and VEGFR-2 Kinases of Cancer by Pharmacokinetics, Toxicity, Molecular Docking, and Molecular Dynamics Simulation.

Vascular endothelial growth factor is an angiogenic that promotes the development and metastasis of tumors (VEGF). The epidermal growth factor receptor, or EGFR, controls the division, growth, and death of cells via several signaling pathways. It has been found that most of the tyrosine kinase EGFR/VEGFR-2 inhibited by drugs that the FDA has approved are so far. The main objective of the present study was to identify an efficacious and selective dual inhibitor of VEGFR-2/EGFR for the treatment of cancer. Out of the 400 ligands tested against the kinases, 12 compounds demonstrated the best docking scores through molecular docking for the two kinases. Of these, only compound SCHEMBL2435814 inhibited the kinases with the highest score values when compared to a reference, vandetanib, as a dual inhibitor of EGFR/VEGFR-2 kinases through interaction with the identified active sites pocket. Following drug-likeness score toxicity and pharmacokinetic testing, the two compounds, SCHEMBL2435814 and vandetanib, were analyzed to determine how the two kinases interacted with each other. The results of calculations of π-cation interactions, hydrogen bonds, and hydrophobic interactions demonstrated a strong interaction between the two kinases and SCHEMBL2435814. Eventually, molecular dynamic modeling was used to assess the stability of complexes. This demonstrated many characteristics, including RMSF, RMSD, SASA, RG, and H-bond analysis, which demonstrated that SCHEMBL2435814 with the two kinases was more stable than vandetanib over a 100ns simulation period. By suppressing EGFR/VEGFR-2, chemical SCHEMBL2435814 may be able to postpone the signaling pathway of proteins that are essential to the advancement of cancer.

Synthesis and in vitro antitumor evaluation of new thieno[2,3-d]pyrimidine derivatives as EGFR and DHFR inhibitors

New thienopyrimidine derivatives 2–16 have been synthesized and their in vitro cytotoxicity was evaluated against five different human cancer cell lines HCT-116, Hela, MDA-MB-231, MCF7 and PC3. Compounds 6e, 7a, 7b, 7d, 10c and 10e displayed the highest antitumor activity against all tested cell lines compared to Doxorubicin. Enzyme inhibition assay revealed that compounds 6e and 10e showed high inhibitory activity against EGFR-TK, with IC50 values of 0.133 and 0.151 µM, compared to Olmutinib (IC50 = 0.028 µM); while the highest DHFR inhibitory activity was shown by compounds 7d and 10e with IC50 values of 0.462 and 0.541 µM, compared to Methotrexate (IC50 = 0.117 µM). Cell cycle analysis following a flow cytometric study using colorectal HCT-116 cancer cell line proved that compound 6e induced cell cycle arrest in G0-G1 phase, while compound 10e arrested the cell cycle at both G0-G1 and S phases. Additionally, both compounds (6e and 10e) were potently able to induce apoptosis in HCT-116 cell line. Docking results of compounds 6e and 10e into the pocket of EGFR active site showed their similar main binding features with Olmutinib, while compounds 7d and 10e showed only moderate fitting into DHFR compared to methotrexate. In silico studies revealed that most of the tested compounds obeyed Lipinski’s RO5 and showed positive drug likeness scores.

Leveraging shape screening and molecular dynamics simulations to optimize PARP1-Specific chemo/radio-potentiators for antitumor drug design

PARP1 plays a pivotal role in DNA repair within the base excision pathway, making it a promising therapeutic target for cancers involving BRCA mutations. Current study is focused on the discovery of PARP inhibitors with enhanced selectivity for PARP1. Concurrent inhibition of PARP1 with PARP2 and PARP3 affects cellular functions, potentially causing DNA damage accumulation and disrupting immune responses. In step 1, a virtual library of 593 million compounds has been screened using a shape-based screening approach to narrow down the promising scaffolds. In step 2, hierarchical docking approach embedded in Schrödinger suite was employed to select compounds with good dock score, drug-likeness and MMGBSA score. Analysis supplemented with decomposition energy, molecular dynamics (MD) simulations and hydrogen bond frequency analysis, pinpointed that active site residues; H862, G863, R878, M890, Y896 and F897 are crucial for specific binding of ZINC001258189808 and ZINC000092332196 with PARP1 as compared to PARP2 and PARP3. The binding of ZINC000656130962, ZINC000762230673, ZINC001332491123, and ZINC000579446675 also revealed interaction involving two additional active site residues of PARP1, namely N767 and E988. Weaker or no interaction was observed for these residues with PARP2 and PARP3. This approach advances our understanding of PARP-1 specific inhibitors and their mechanisms of action, facilitating the development of targeted therapeutics.

IN SILICO EXPLORATION OF BERBERINE AS A POTENTIAL WOUND HEALING AGENT VIA NETWORK PHARMACOLOGY, MOLECULAR DOCKING, AND MOLECULAR DYNAMICS SIMULATION

Objective: Wound healing remains a complex biological process crucial for tissue repair and homeostasis. Our goal in this paper is to focus on the application of advanced computational techniques to explore the potential of naturally occurring compound berberine in addressing molecular targets related to wound healing. Methods: Network pharmacology, molecular docking analysis, in silico ADMET prediction, and extensive 100 ns molecular dynamics simulations was performed to gain a holistic understanding of the therapeutic potential of berberine against molecular targets involved in wound healing. This study predicted drug-likeness scores, potential side effects, ADMET profiles, carcinogenicity, MolLogP, molecular volume analysis, and molecular polar surface area for berberine. Results: Findings of the study revealed that berberine displayed a remarkable binding affinity for the epidermal growth factor receptor (EGFR), with a binding energy of-8.14 kcal/mol, surpassing the crystal ligand's binding energy of-7.15 kcal/mol. This indicates a strong potential for berberine in modulating EGFR-related pathways critical for wound healing. The culmination of the investigation was a 100 ns molecular dynamics simulation, which demonstrated consistent binding and stability over time, reinforcing the potential of berberine as a wound healing agent. Conclusion: The integration of gene expression analysis, enrichment studies, network analysis, molecular docking, and molecular dynamics simulations unveiled crucial mechanisms underlying efficacy of berberine as a potent wound-healing agent.

Synthesis, spectroscopic analysis, and computational-based investigations on ‘azo-coumarin-Co(II)-galangin’ hybrids exhibit multipotential activities

The present study synthesized a series of cobalt (II) metal ion frame hybrid candidates (6a–6f) bearing phyto-flavonol galangin with substituted aryl diazenyl coumarins, and further structural confirmation was validated by various spectral techniques, including NMR, ATR-FTIR, UV-vis, HPLC, XRD, etc. Therapeutic potency was investigated via PASS (prediction of activity spectra for substances), molecular docking, molecular dynamics simulation, prediction of toxicity, pharmacokinetics, and drug-likeness scores, along with the highest occupied molecular orbital (HOMO), the lowest unoccupied molecular orbital (LUMO), with their energy gaps (ΔEH–L) to locate the most potential therapeutic candidates. The PASS prediction (Pa > Pi score) showed that proposed metal complexes have kinase inhibitors, antioxidative, and antischistosomal activities with potential molecular docking scores (> −7 kcal/mol) against selected targeted enzymes. Further, the MD-simulation (RMSD, RMSF, Rg, and H-bonds) of the most potential docking complex, ‘HER2-6d’, showed a minimum deviation similar to the standard drug (lapatinib) at 100 ns, indicating that 6d could be a potential noncovalent anticancer inhibitor. In addition, metal complexes possess a non-toxic and ideal drug-ability profiles, and positive electron space in an excited state increases the binding affinity towards target enzymes. Among all six ligands, 6c and 6d were the two most multipotent therapeutic agents from the above analyses. In summary, this could be a feasible approach towards the utilization of phytochemicals in mainstream therapeutic applications, where bioinformatics tools help to select a lead drug candidate at an early stage and guide for higher experimental success by proceeding with potential candidates. Communicated by Ramaswamy H. Sarma

Synthesis, in silico screening, and biological evaluation of novel pyridine congeners as anti-epileptic agents targeting AMPA (α-amino-3-hydroxy-5-methylisoxazole) receptors.

The research involves the synthesis of a series of new pyridine analogs 5(i-x) and their evaluation for anti-epileptic potential using in silico and invivo models. Synthesis of the compounds was accomplished by using the Vilsmeier-Haack reaction principle. AutoDock 4.2 was used for their in silico screening against AMPA (-amino-3-hydroxy-5-methylisoxazole) receptor (PDB ID:3m3f). For invivo testing, the maximal electroshock seizure (MES) model was used. The physicochemical, pharmacokinetic, drug-like, and drug-score features of all synthesized compounds were assessed using the online Swiss ADME and Protein Plus software. The in silico results showed that all the synthesized compounds 5(i-x) had 1-3 interactions and affinities ranging from -6.5 to -8.0 kJ/mol with the targeted receptor compared to the binding affinities of the standard drug phenytoin and the original ligand of the target (P99), which were -7.6 and -6.8 kJ/mol, respectively. Invivo study results showed that the compound 5-Carbamoyl-2-formyl-1-[2-(4-nitrophenyl)-2-oxo-ethyl]-pyridinium gave 60% protection against epileptic seizures compared to 59% protection afforded by regular phenytoin. All of them met Lipinski's rule of five and had drug-likeness and drug score values of 0.55 and 0.8, respectively, making them chemically and functionally like phenytoin. According to the findings of the studies, the synthesized derivatives have the potential to be employed as a stepping stone in the development of novel anti-epileptic drugs.

Target-Based 6-5 Fused Ring Heterocyclic Scaffolds Display Broad Antiparasitic Potency In Vitro

Malaria, leishmaniasis, and African trypanosomiasis are protozoan diseases that constitute major global health problems, especially in developing countries; however, the development of drug resistance coupled with the toxicity of current treatments has hindered their management. The involvement of certain enzymes (dihydrofolate reductase [DHFR]) or proteins (potassium channels) in the pathogenesis of these protozoan diseases is undeniable. In this study, a series of three DHFR inhibitors (6-5 fused heterocyclic derivatives X, Y, and Z) and one K+ channel blocker (E4031) were screened for their inhibitory effects on Leishmania donovani, Plasmodium falciparum, and Trypanosoma brucei. A resazurin assay was used to assess the antitrypanosomal and antileishmanial activities of the test compounds, whereas the antiplasmodial activity was evaluated through the SYBR Green I test. Moreover, the cytotoxicities of the test compounds were evaluated in Vero, Raw 264.7, and HepG-2 cells using a resazurin-based test, while their pharmacokinetic properties were predicted using the online tool, pkCSM. As a result, compound Y exhibited selective (selectivity index range: from 2.69 to &gt;61.4; Vero, Raw 264.7, and HepG-2 cells) and broad-spectrum antiprotozoal activity against L. donovani promastigotes (IC50: 12.4 µM), amastigotes (IC50: 4.28 µM), P. falciparum (IC50: 0.028 µM), and T. brucei brucei (IC50: 0.81 µM). In addition, compound X inhibited the growth of P. falciparum (IC50: 0.0052 µM) and T. brucei brucei (IC50: 6.49 µM). In silico screening of the active antiprotozoal compounds revealed positive drug likeness scores, as none of the criteria for Lipinski’s rule were violated by these compounds. However, in-depth pharmacokinetic and mechanistic studies are warranted to support the discovery of novel antiprotozoal agents against malaria, leishmaniasis, and African trypanosomiasis by repurposing K+ channel blockers and DHFR inhibitors.