Insights from in silico exploration of major curcumin analogs targeting human dipeptidyl peptidase IV

The goal of this work is to use a variety of in-silico techniques to identify anti-diabetic agents against DPP-IV enzyme from five main curcumin analogues. To produce the successful molecules, five main curcumin analogues were docked into the active site of DPP-IV enzyme. In comparison to the control molecule (Saxagliptin, −6.9 kcal/mol), all the compounds have the highest binding affinity (-7.6 to −7.7 kcal/mol) for the DPP-IV enzyme. These compounds underwent further testing for studies on drug-likeness, pharmacokinetics, and acute toxicity to see the efficacy and safety of compounds. To assess the stability of the docking complex and the binding posture identified during the docking experiment, our study got THC as the lead compound, which was then exposed to 200 ns of molecular dynamic simulation and PCA analysis. Additionally, DFT calculations were conducted to determine the thermodynamic, molecular orbital, and electrostatic potential characteristics of lead compound. Overall, the lead chemical has shown strong drug-like properties, is non-toxic, and has a sizable affinity for the DPP-IV enzyme

Computer-aided anti-cancer drug discovery of EGFR protein based on virtual screening of drug bank, ADMET, docking, DFT and molecular dynamic simulation studies

Numerous malignancies, including breast cancer, non-small cell lung cancer, and chronic myeloid leukemia, are brought on by aberrant tyrosine kinase signaling. Since the current chemotherapeutic medicines are toxic, there is a great need and demand from cancer patients to find novel chemicals that are toxic-free or have low toxicity and that can kill tumor cells and stop their growth. This work describes the in-silico examination of substances from the drug bank as EGFR inhibitors. Firstly, drug-bank was screened using the pharmacophore technique to select the ligands and Erlotinib (DB00530) was used as matrix compound. The selected ligands were screened using ADMET and the hit compounds were subjected to docking. The lead compound from the docking was subjected to DFT and MD simulation study. Using the pharmacophore technique, 23 compounds were found through virtual drug bank screening. One hit molecule from the ADMET prediction was the subject of docking study. According to the findings, DB03365 molecule fits to the EGFR active site by several hydrogen bonding interactions with amino acids. Furthermore, DFT analysis revealed high reactivity for DB03365 compound in the binding pocket of the target protein, based on ELUMO, EHOMO and band energy gap. Furthermore, MD simulations for 100 ns revealed that the ligand interactions with the residues of EGFR protein were part of the essential residues for structural stability and functionality. However, DB03365 was a promising lead molecule that outperformed the reference compound in terms of performance and in-vitro and in-vivo experiments needs to validate the study

Polypharmacological assessment of amoxicillin and its analogues against the bacterial DNA gyrase B using molecular docking, DFT and molecular dynamics simulation

There has been an increase in the emergence and spread of drug-resistant pathogens, leading to a steep incline in the cases of antimicrobial resistance. Due to this, there is an imperative need for the development and identification of new antimicrobials to combat this menace of antimicrobial resistance. But this need is not being completely fulfilled by conventional drug discovery focused on a one molecule-one target approach. Polypharmacology, i.e., designing a drug in a way that acts on multiple cellular or molecular targets, a new approach for the identification of antimicrobial compounds, has been gaining attention. DNA gyrase B is one of the critical proteins involved in DNA replication and cell division in E. coli. In this study, the polypharmacological effect of amoxicillin and its analogues was studied on the DNA gyrase B and various other proteins of E. coli, using multiple in silico approaches like molecular docking, structural similarity, DFT, and molecular dynamics simulation. Both amoxicillin and its analogue, Cefaclor, tend to disrupt bacterial cell wall synthesis, but this study, based on in silico analysis, suggests a probable additional mode of action involving DNA gyrase B of E. coli which can be further explored to design novel dual-target inhibitors

Computational evaluation of quinones of Nigella sativa L. as potential inhibitor of dengue virus NS5

Aedes aegypti is the primary vector for the transmission of the dengue virus, which causes dengue fever, dengue hemorrhagic illness and dengue shock syndrome. There is now no antiviral medication available to treat DENV, which kills thousands of people each year and infects millions of individuals. A possible target for the creation of fresh and efficient dengue treatments is the DENV-3 NS5 MTase. So, Nigella sativa quinones were examined using in silico methods to find natural anti-DENV compounds. The in silico docking was conducted utilising the Discovery Studio software on the quinones of N. sativa and the active site of the target protein DENV-3 NS5 MTase. In addition, the druggability and pharmacokinetics of the lead compound were assessed. Dithymoquinone was comparable to the reference compound in terms of its ability to bind to the active site of target protein. Dithymoquinone met the requirements for drug likeness and Lipinski’s principles, as demonstrated by the ADMET analysis and drug likeness results. The current study indicated that the dithymoquinone from N. sativa had anti-DENV activity, suggesting further drug development and dengue treatment optimisatio

Phenolic compounds of Theobroma cacao L. show potential against dengue RdRp protease enzyme inhibition by In-silico docking, DFT study, MD simulation and MMGBSA calculation

Background: Currently, there is no antiviral medication for dengue, a potentially fatal tropical infectious illness spread by two mosquito species, Aedes aegypti and Aedes albopictus. The RdRp protease of dengue virus is a potential therapeutic target. This study focused on the in silico drug discovery of RdRp protease inhibitors. Methods; To assess the potential inhibitory activity of 29 phenolic acids from Theobroma cacao L. against DENV3-NS5 RdRp, a range of computational methods were employed. These included docking, drug-likeness analysis, ADMET prediction, density functional theory (DFT) calculations, and molecular dynamics (MD) simulations. The aim of these studies was to confirm the stability of the ligand-protein complex and the binding pose identified during the docking experiment. Results: Twenty-one compounds were found to have possible inhibitory activities against DENV according to the docking data, and they had a binding affinity of ≥-37.417 kcal/mol for DENV3- enzyme as compared to the reference compound panduratin A. Additionally, the drug-likeness investigation produced four hit compounds that were subjected to ADMET screening to obtain the lead compound, catechin. Based on ELUMO, EHOMO, and band energy gap, the DFT calculations showed strong electronegetivity, favouravle global softness and chemical reactivity with considerable intra-molecular charge transfer between electron-donor to electron-acceptor groups for catechin. The MD simulation result also demonstrated favourable RMSD, RMSF, SASA and H-bonds in at the binding pocket of DENV3-NS5 RdRp for catechin as compared to panduratin A. Conclusion: According to the present findings, catechin showed high binding affinity and sufficient drug-like properties with the appropriate ADMET profiles. Moreover, DFT and MD studies further supported the drug-like action of catechin as a potential therapeutic candidate. Therefore, further in vitro and in vivo research on cocoa and its phytochemical catechin should be taken into consideration to develop as a potential DENV inhibitor

Pharmacophore-based virtual screening and in-silico study of natural products as potential DENV-2 RdRp inhibitors

Dengue fever is a significant public health concern throughout the world, causing an estimated 500,000 hospitalizations and 20,000 deaths each year, despite the lack of effective therapies. The DENV-2 RdRp has been identified as a potential target for the development of new and effective dengue therapies. This research’s primary objective was to discover an anti-DENV inhibitor using in silico ligand- and structure-based approaches. To begin, a ligand-based pharmacophore model was developed, and 130 distinct natural products (NPs) were screened. Docking of the pharmacophore-matched compounds were performed to the active site of DENV-2 RdRp protease . Eleven compounds were identified as potential DENV-2 RdRp inhibitors based on docking energy and binding interactions. ADMET and drug-likeness were done to predict their pharmacologic, pharmacokinetic, and drug-likeproperties . Compounds ranked highest in terms of pharmacokinetics and drug-like appearances were then subjected to additional toxicity testing to determine the leading compound. Additionally, MD simulation of the lead compound was performed to confirm the docked complex’s stability and the binding site determined by docking. As a result, the lead compound (compound-108) demonstrated an excellent match to the pharmacophore, a strong binding contact and affinity for the RdRp enzyme, favourable pharmacokinetics, and drug-like characteristics. In summary, the lead compound identified in this study could be a possible DENV-2 RdRp inhibitor that may be further studied on in vitro and in vivo models to develop as a drug candidate

Investigation of antituberculosis, antimicrobial, anti-inflammatory efficacies of newly synthesized transition metal(II) complexes of hydrazone ligands: structural elucidation and theoretical studies

Abstract Tuberculosis disease is a serious threat to humans and spreading quickly worldwide, therefore, to find a potent drug, the synthesis of hydrazone ligands endowed Co(II), Ni(II), Cu(II), Zn(II) metal complexes were carried out and well characterized by numerous spectral and analytical techniques. The octahedral geometry of the complexes was confirmed by spectral analysis. Further, in vitro antituberculosis efficacy of the compounds (1–10) revealed that complexes (6), (9), (10) have highest potency to control TB malformation with 0.0028 ± 0.0013–0.0063 ± 0.0013 µmol/mL MIC value while Zn(II) complex (10) (0.0028 ± 0.0013 µmol/mL) has nearly four time potent to suppress TB disease in comparison of streptomycin (0.0107 ± 0.0011 µmol/mL). The antimicrobial and anti-inflammatory evaluations revealed that the complex (10) is more active with lowest MIC (0.0057–0.0114 µmol/mL) and IC50 (7.14 ± 0.05 µM) values, correspondingly which are comparable with their respective standard drugs. Furthermore, the theoretical studies such as molecular docking, DFT, MESP and ADMET were employed to authenticate the potency of HL 2 hydrazone ligand (2) and its metal complexes (7–10) which revealed that the zinc(II) complex (10) might be utilized as novel drug candidate for tuberculosis dysfunctions. So, the present research gives a new insight for in vivo investigation of the compounds

Synthesis, spectroscopic findings, SEM/EDX, DFT, and single-crystal structure of Hg/Pb/Cu–SCN complexes: In silico ADME/T profiling and promising antibacterial activities

This work contemplates synthesizing M-SCN crystal compounds (M = Hg/Pb/Cu) in the presence of respective metal salts and exogenous ancillary SCN− ion by slowly evaporating the mixed solvent (CH3OH + ACN). The complexes were characterized by spectroscopy, SEM/EDX, and X-ray crystallography. The Hg-Complex, Pb-Complex, and Cu-Complex crystallize in the monoclinic space group (Z = 2/4). The crystal packing fascinatingly consists of weak covalent bonding and Pb⋯S contacts of tetrel type bond. Here are the incredible supramolecular topographies delineated by the Hirshfeld surface and 2D fingerprint plot. The B3LYP/6–311++G (d, p) level calculations in the gas phase optimized the compound's geometry. The energy difference (Δ) between HOMO-LUMO and global reactivity parameters investigates the complex's energetic activity. MESP highlights the electrophilic/nucleophilic sites and H-bonding interactions. Molecular docking was conceded with the Gram- + ve bacterium Bacillus Subtilis (PDB ID: 6UF6) and the Gram-ve bacterium Proteus Vulgaris (PDB ID: 5HXW) to authenticate the bactericidal activity. ADME/T explains the various pharmacological properties. In addition, we studied the antibacterial activity with MIC (μg/mL) values and time-kill kinetics against Staphylococcus aureus (ATCC 25923) and Bacillus subtilis (ATCC 6635) as Gram-positive, Pseudomonas aeruginosa (ATCC 27853) and Escherichia coli (ATCC 25922) as Gram-negative bacteria

Insights from <i>in silico</i> exploration of major curcumin analogs targeting human dipeptidyl peptidase IV

The goal of this work is to use a variety of in-silico techniques to identify anti-diabetic agents against DPP-IV enzyme from five main curcumin analogues. To produce the successful molecules, five main curcumin analogues were docked into the active site of DPP-IV enzyme. In comparison to the control molecule (Saxagliptin, −6.9 kcal/mol), all the compounds have the highest binding affinity (-7.6 to −7.7 kcal/mol) for the DPP-IV enzyme. These compounds underwent further testing for studies on drug-likeness, pharmacokinetics, and acute toxicity to see the efficacy and safety of compounds. To assess the stability of the docking complex and the binding posture identified during the docking experiment, our study got THC as the lead compound, which was then exposed to 200 ns of molecular dynamic simulation and PCA analysis. Additionally, DFT calculations were conducted to determine the thermodynamic, molecular orbital, and electrostatic potential characteristics of lead compound. Overall, the lead chemical has shown strong drug-like properties, is non-toxic, and has a sizable affinity for the DPP-IV enzyme. Communicated by Ramaswamy H. Sarma</p