Molecular Mechanics-generalized Surface Area Research Articles

3D-QSAR Combination with Molecular Dynamics Simulations to Effectively Design the Active Ryanodine Receptor Agonists against Spodoptera frugiperda.

Computer-aided molecular modeling was applied to design a series of Spodoptera frugiperda RyR agonists. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used to generate 3D-QSAR models. MD simulations in the complex with S. frugiperda native, mutant RyR, and mammalian RyR1 under physiological conditions were used to validate the detailed binding mechanism. Binding free energy calculation by molecular mechanics generalized surface area (MM-GBSA) explained the role of key amino acid residues in ligand-receptor binding. Therefore, 14 new compounds were effectively designed and synthesized, and a bioassay indicated that compounds A-2 and A-3 showed comparable activity to that of chloranthraniliprole with LC50 values of 0.27, 0.18, and 0.20 mg L-1, respectively, against S. frugiperda. Most target compounds also displayed good activity against Mythinma separata at 0.1 mg L-1. Molecular docking and MM-GBSA calculations demonstrated that A-3 had a better binding capacity with native and mutant S. frugiperda RyRs.

Identification of some bioactive compounds from Trignonella foenumgraecum as possible inhibitors of PPARϒ for diabetes treatment through molecular docking studies, pharmacophore modelling and ADMET profiling: An in-silico study.

Oral antidiabetic agents including the peroxisome proliferator-activated receptor gamma (PPARγ) agonists are available for the clinical management of diabetes mellitus (DM) but most are characterized by many adverse effects. In this study, we explore the antidiabetic properties of phytoconstituents from Trigonellafeonumgraecum (Fabaceae) as potential agonist of PPARγ; using in silico molecular docking, molecular mechanics generalized surface area (MM/GBSA)free binding energy prediction, Pharmacophore modeling experiment, and Pharmacokinetic/ toxicity analysis. One hundred and forty (140) compounds derived from Trigonellafeonumgraecum were screened by molecular docking against protein target PDB 3VI8. Results obtained from binding affinity (BA) and that of binding free energy (BFE) revealed five 5 compounds; arachidonic acid (CID_10467, BA -10.029, BFE -58.9), isoquercetin (CID_5280804, BA -9.507kcal/mol, BFE -56.33), rutin (CID_5280805, BA -9.463kcal/mol, BFE -56.33), quercetin (CID_10121947, BA -11.945kcal/mol, BFE -45.89) and (2S)-2-[[4-methoxy-3-[(pyrene-1-carbonylamino)methyl]phenyl]methyl]butanoic acid (CID_25112371, BA -10.679kcal/mol, BFE -45.73); and were superior to the standard; Rosiglitazone with a docking score of -7.672. Hydrogen bonding was notable in the protein-ligand complex interaction, with hydrophobic bond, polar bond and pipi stacking also observed. Their Pharmacokinetic/ toxicity profile showed varying druggable characteristics, but; arachidonic acid had the most favorable characteristics. These compounds are potential agonists of PPARγ and are considered as antidiabetic agents after successful experimental validation.

Complexation of methotrexate via ligand diffusion molecular dynamic simulations under neutral, basic, and acidic conditions

Methotrexate (MTX), an FDA-approved drug employed in the treatment of several types of cancer and autoimmune diseases, is characterized by its poor solubility. Therefore, new strategies have been implemented such as coupling to nanocarriers to increase its solubility. Previous experimental studies have demonstrated complexation of MTX to polyamidoamine of a generation four (PAMAM-G4) dendrimer with a complex stoichiometry of 19/22:1 under neutral conditions, providing important information that can be used to further elucidate the structural and energetic basis of the molecular binding of MTX and PAMAM-G4. In this study, we performed ligand diffusion molecular dynamic simulations (LDMDSs), using 3 μs combined with the molecular mechanics generalized surface area (MMGBSA) approach employing saturating concentrations of MTX to explore the mechanism through which MTX is complexed by PAMAM-G4 at neutral, basic, and acidic conditions. Our results reproduce the reported complex stoichiometry between MTX and PAMAM-G4 in neutral conditions. Binding free energy values suggest a much slower release in neutral and acidic conditions, consistent with the controlled rate of drug release into the bloodstream and when reaching the acidic environment of tumor tissues. Altogether, the methodology employed and the results may be useful in the evaluation of other drugs of pharmaceutical interest.