'Synthesis, antiviral activity, molecular docking, and molecular dynamics studies of ethoxy phthalimide pyrazole derivatives against Cytomegalovirus and Varicella-Zoster virus: potential consequences and strategies for developing new antiviral treatments'.

Substituted ethoxy phthalimide pyrazole derivatives (6a-e) have been produced using a one-pot synthesis technique. Spectral analysis was used to establish the molecular structure of the synthesized compounds, and they were examined in silico and in vitro for their ability to bind to and inhibit replication of the AD-169 strain, the Davis strain of CMV, the OKA strain and the 07/1 strain of Varicella-Zoster virus (VZV). Molecular Docking was used to estimate the binding mechanism and energy of compounds 4, 6a-e to their respective target proteins, thymidine kinase (TK), Varicella-Zoster protease (VZP) of VZV and tegument protein pp71 (TPpp71) of Cytomegalovirus (CMV). The MIC50 and EC50 were utilized to evaluate the antiviral and cytotoxic activities of test compounds in human embryonic lung (HEL) cells against the two reference medicines, Ganciclovir and Acyclovir. The chemicals studied showed a high affinity for binding sites and near binding sites of target proteins by generating H-bonds, carbon-hydrogen bonds, π-anion, π-sulfur, π-sigma, alkyl and π-alkyl interactions. All of the test compounds (6a-e) had higher binding energy than the standard medications. The ADME/T data suggests that these potential inhibitors are less toxic. Drug-protein complexes are structurally compact and demonstrate minimal conformational change in molecular dynamics (MDs) simulations, indicating stability and stiffness. MM-PBSA and post-simulation analysis can predict lead compound active cavity binding stability. By inhibiting multitargeted proteins, these synthetic compounds may improve antiviral therapy. Our research suggests that these unique synthesized chemicals may be useful and accessible adjuvant antiviral therapy for Varicella Zoster and CMV. HighlightsTwo components synthesis of substituted ethoxy phthalimide pyrazole derivatives (6a-e).Tested compounds (6a-e) have antiviral and cytotoxicity activity against CMV and Varicella-Zoster virus (VZV) in HEL cells.Compounds bind to TK, Varicella-Zoster protease (VZP) of VZV, and modeled TPpp71 of Cytomegalovirus (CMV).In comparison to reference drugs, compounds have strong binding free energy and interactions with VZV and CMV protein complexes.The RMSD, RMSF, Rg, residual correlative motion (RCM), No. of hydrogen bonds, protein secondary structure content, per-residue protein secondary structure and MM/PBSA energy calculated for the selected compound with thymidine kinase (TK), VZP of VZV, and modeled tegument protein pp71 (TPpp71) of CMV through MD simulation studies for 50 ns.In comparison to the two reference drugs, ligands/compounds were found to meet the Lipinski rule of five and to have strong biological activity.Communicated by Ramaswamy H. Sarma.

"In silico identification of ethoxy phthalimide pyrazole derivatives as IL-17A and IL-18 targeted gouty arthritis agents".

Two proinflammatory cytokines, IL17A and IL18, are observed to be elevated in the serum of gout patients and they play a crucial role in the development and worsening of inflammation, which has severe effects. In present study, we have combined molecular docking, molecular dynamics studies and MM-PBSA analysis to study the effectiveness of ethoxy phthalimide pyrazole derivatives (series 3a to 3e) as potential inhibitors against cytokines IL17A and IL18 as a druggable targets. The binding energy of the docked series ranges from -13.5 to -10.0 kcal/mol and extensively interacts with the amino acids in the active pocket of IL17A and IL18. Compound 3e had the lowest binding energy with IL17A at -12.6 kcal/mol compared to control allopurinol (3.32 kcal/mol). With IL18, compound 3a seems to have the lowest binding energy of -9.6 kcal/mol compared to control allopurinol (3.18 kcal/mol). In MD simulation studies, compound 3a forms a stable and energetically stabilized complex with the target protein. Depending on properties of the bound IL17A-3a and IL18-3a complexes was compared by means of MM-PBSA analysis. These derivatives can be used as a scaffold to develop promising IL17A and IL18 inhibitors to assess their potential for gouty arthritis and other related diseases. Communicated by Ramaswamy H. Sarma.

Identification of 1, 2, 4-Triazine and Its Derivatives Against Lanosterol 14-Demethylase (CYP51) Property of Candida albicans: Influence on the Development of New Antifungal Therapeutic Strategies.

This research aims to find out whether the 1, 2, 4-triazine and its derivatives have antifungal effects and can protect humans from infection with Candida albicans. Molecular docking and molecular dynamic simulation are widely used in modern drug design to target a particular protein with a ligand. We are interested in using molecular docking and molecular dynamics modeling to investigate the interaction between the derivatives of 1, 2, 4-triazine with enzyme Lanosterol 14-demethylase (CYP51) of Candida albicans. The inhibition of Candida albicans CYP51 is the main goal of our research. The 1, 2, 4-triazine and its derivatives have been docked to the CYP51 enzyme, which is involved in Candida albicans Multidrug Drug Resistance (MDR). Autodock tools were used to identify the binding affinities of molecules against the target proteins. Compared to conventional fluconazole, the molecular docking results indicated that each drug has a high binding affinity for CYP51 proteins and forms unbound interactions and hydrogen bonds with their active residues and surrounding allosteric residues. The docking contacts were made using a 10 ns MD simulation with nine molecules. RMSD, RMSF, hydrogen bonds, and the Rg all confirm these conclusions. In addition, these compounds were expected to have a favorable pharmacological profile and low toxicity. The compounds are being offered as scaffolds for the development of new antifungal drugs and as candidates for future in vitro testing.

Identification of novel inhibitors of high affinity iron permease (FTR1) through implementing pharmacokinetics index to fight against black fungus: An in silico approach.

Mucormycosis is a life-threatening fungal infection, particularly in immunocompromised patients. Mucormycosis has been reported to show resistance to available antifungal drugs and was recently found in COVID-19 as a co-morbidity that demands new classes of drugs. In an attempt to find novel inhibitors against the high-affinity iron permease (FTR1), a novel target having fundamental importance on the pathogenesis of mucormycosis, 11,000 natural compounds were investigated in this study. Virtual screening and molecular docking identified two potent natural compounds [6',7,7,10',10',13'-hexamethylspiro[1,8-dihydropyrano[2,3-g]indole-3,11'-3,13-diazatetracyclo[5.5.2.01,9.03,7]tetradecane]-2,9,14'-trione and 5,7-dihydroxy-3-(2,2,8,8-tetramethylpyrano[2,3-f]chromen-6-yl)chromen-4-one] that effectively bind to the active cavity of FTR1 with a binding affinity of -9.9 kcal/mol. Multiple non-covalent interactions between the compounds and the active residues of this cavity were noticed, which is required for FTR1 inhibition. These compounds were found to have inhibitory nature and meet essential requirements to be drug-like compounds with a considerable absorption, distribution, metabolism, and excretion (ADME) profile with no toxicity probabilities. Molecular dynamics simulation confirms the structural compactness and less conformational variation of the drug-protein complexes maintaining structural stability and rigidity. MM-PBSA and post-simulation analysis predict binding stability of these compounds in the active cavity. This study hypothesizing that these compounds could be a potential inhibitor of FTR1 and will broaden the clinical prospects of mucormycosis.

Unlocking SGK1 inhibitor potential of bis-[1-N,7-N, pyrazolo tetraethoxyphthalimido{-4-(3,5-Dimethyl-4-(spiro-3-methylpyazolo)-1,7-dihydro-1H-dipyrazolo[3,4-b;4',3'-e]pyridin-8-yl)}]p-disubstituted phenyl compounds: a computational study.

SGK1 (Serum and Glucocorticoid Regulated Kinase 1), a serine/threonine kinase that is activated by various stimuli, including serum and glucocorticoids. It controls inflammation, apoptosis, hormone release, neuro-excitability and cell proliferation, all of which play an important role in cancer progression and metastasis. SGK1 was recently proposed as a potential drug target for cancer, diabetes, and neurodegenerative diseases. In this study, molecular docking, physiochemical, toxicological properties and molecular dynamic simulation of the Bis-[1-N,7-N, Pyrazolo tetraethoxyphthalimido{-4-(3,5-Dimethyl-4-(spiro-3-methylpyazolo)-1,7-dihydro-1H-dipyrazolo[3,4-b;4',3'-e]pyridin-8-yl)}]p-disubstituted phenyl compoundsand reference EMD638683 against new SGK1 target protein. Compared to the reference inhibitor EMD638683, we choose the best compounds (series 2-6) based on the binding energy (in the range from -11.0 to -10.6 kcal/mol). With the exception of compounds 2 and 6, none of the compounds posed a risk for AMES toxicity or carcinogenicity due to their toxicological properties. 100 ns MD simulation accompanied by MM/PBSA energy calculations and PCA. According to MD simulation results, the binding of compounds 3, 4 and 5 stabilizes the SGK1 structure and causes febrile conformational changes compared to EMD638683. As a result of this research, the final selected compounds 3, 4 and 5 can be used as scaffolds to develop promising SGK1 inhibitors for the treatment of related diseases such as cancer.Communicated by Ramaswamy H. Sarma.

Molecular docking and simulation studies of flavonoid compounds against PBP-2a of methicillin-resistant Staphylococcus aureus.

Methicillin-Resistant Staphylococcus aureus (MRSA), a pathogenic bacterium that causes life-threatening outbreaks such as community-onset and nosocomial infections as emerging 'superbug'. Time and motion study of its virulent property developed resistance against most of the antibiotics such as Vancomycin. Thereby, to curb this problem entails the development of new therapeutic agents. Plant-derived antimicrobial agents have recently piqued people's interest, so in this research, 186 flavonoids compound selected to unmask the best candidates that can act as potent inhibitors against the Penicillin Binding Protein-2a (PBP-2a) of MRSA. Molecular docking performed using PyRx and GOLD suite to determine the binding affinities and interactions between the phytochemicals and the PBP-2a. The selected candidates strongly interact with the different amino acid residues. The 30 ns molecular dynamics (MD) simulations with five top-ranked compounds such as Naringin, Hesperidin, Neohesperidin, Didymin and Icariin validated the docking interactions. These findings are also strongly supported by root-mean-square deviation, root-mean-square fluctuation and the radius of gyration. ADME/T analysis demonstrates that these candidates appear to be safer inhibitors. Our findings point to natural flavonoids as a promising and readily available source of adjuvant antimicrobial therapy against resistant strains in the future.Communicated by Ramaswamy H. Sarma.