Predictive Models for Maximum Recommended Therapeutic Dose of Antiretroviral Drugs

A novel method for predicting maximum recommended therapeutic dose (MRTD) is presented using quantitative structure property relationships (QSPRs) and artificial neural networks (ANNs). MRTD data of 31 structurally diverse Antiretroviral drugs (ARVs) were collected from FDA MRTD Database or package inserts. Molecular property descriptors of each compound, that is, molecular mass, aqueous solubility, lipophilicity, biotransformation half life, oxidation half life, and biodegradation probability were calculated from their SMILES codes. A training set (n = 23) was used to construct multiple linear regression and back propagation neural network models. The models were validated using an external test set (n = 8) which demonstrated that MRTD values may be predicted with reasonable accuracy. Model predictability was described by root mean squared errors (RMSEs), Kendall's correlation coefficients (tau), P-values, and Bland Altman plots for method comparisons. MRTD was predicted by a 6-3-1 neural network model (RMSE = 13.67, tau = 0.643, P = 0.035) more accurately than by the multiple linear regression (RMSE = 27.27, tau = 0.714, P = 0.019) model. Both models illustrated a moderate correlation between aqueous solubility of antiretroviral drugs and maximum therapeutic dose. MRTD prediction may assist in the design of safer, more effective treatments for HIV infection

Preparation, Spectrochemical, and Computational Analysis of L-Carnosine (2-[(3-Aminopropanoyl)amino]-3-(1H-imidazol-5-yl)propanoic Acid) and Its Ruthenium (II) Coordination Complexes in Aqueous Solution

This study reports the synthesis and characterization of novel ruthenium (II) complexes with the polydentate dipeptide, L-carnosine (2-[(3-aminopropanoyl)amino]-3-(1H-imidazol-5-yl)propanoic acid). Mixed-ligand complexes with the general composition [MLp(Cl)q(H2O)r]·xH2O (M = Ru(II); L = L-carnosine; p = 3 − q; r = 0–1; and x = 1–3) were prepared by refluxing aqueous solutions of the ligand with equimolar amounts of ruthenium chloride (black-alpha form) at 60 °C for 36 h. Physical properties of the complexes were characterized by elemental analysis, DSC/TGA, and cyclic voltammetry. The molecular structures of the complexes were elucidated using UV-Vis, ATR-IR, and heteronuclear NMR spectroscopy, then confirmed by density function theory (DFT) calculations at the B3LYP/LANL2DZ level. Two-dimensional NMR experiments (1H COSY, 13C gHMBC, and 15N gHMBC) were also conducted for the assignment of chemical shifts and calculation of relative coordination-induced shifts (RCIS) by the complex formed. According to our results, the most probable coordination geometries of ruthenium in these compounds involve nitrogen (N1) from the imidazole ring and an oxygen atom from the carboxylic acid group of the ligand as donor atoms. Additional thermogravimetric and electrochemical data suggest that while the tetrahedral-monomer or octahedral-dimer are both possible structures of the formed complexes, the metal in either structure occurs in the (2+) oxidation state. Resulting RCIS values indicate that the amide-carbonyl, and the amino-terminus of the dipeptide are not involved in chelation and these observations correlate well with theoretical shift predictions by DFT

Phosphine-Free Tetradentate Salicylaldimine Ligand Complexed with Palladium: First Application in Heck Reactions

<div><p></p><p>Heck reactions were carried out using phosphine-free tetradentate salicylaldimine ligand complexed with PdCl₂ under mild reaction conditions, short reaction time, and low palladium loading. All aryl iodides underwent coupling reactions with olefins, giving corresponding <i>trans</i>-products, with good to excellent yields, whereas aryl bromides gave very poor yields and aryl chlorides failed to react.</p> </div

Formulation and Molecular Dynamics Simulations of a Fusidic Acid Nanosuspension for Simultaneously Enhancing Solubility and Antibacterial Activity

The aim of the present study was to formulate a nanosuspension (FA-NS) of fusidic acid (FA) to enhance its aqueous solubility and antibacterial activity. The nanosuspension was characterized using various in vitro, in silico, and in vivo techniques. The size, polydispersity index, and zeta potential of the optimized FA-NS were 265 ± 2.25 nm, 0.158 ± 0.026, and −16.9 ± 0.794 mV, respectively. The molecular dynamics simulation of FA and Poloxamer-188 showed an interaction and binding energy of −74.42 kJ/mol and −49.764 ± 1.298 kJ/mol, respectively, with van der Waals interactions playing a major role in the spontaneous binding. There was an 8-fold increase in the solubility of FA in a nanosuspension compared to the bare drug. The MTT assays showed a cell viability of 75–100% confirming the nontoxic nature of FA-NS. In vitro antibacterial activity revealed a 16- and 18-fold enhanced activity against <i>Staphylococcus aureus</i> (SA) and methicillin-resistant SA (MRSA), respectively, when compared to bare FA. Flowcytometry showed that MRSA cells treated with FA-NS had almost twice the percentage of dead bacteria in the population, despite having an 8-fold lower MIC in comparison to the bare drug. The in vivo skin-infected mice showed a 76-fold reduction in the MRSA load for the FA-NS treated group compared to that of the bare FA. These results show that the nanosuspension of antibiotics can enhance their solubility and antibacterial activity simultaneously

Antimicrobial cell penetrating peptides with bacterial cell specificity: pharmacophore modelling, quantitative structure activity relationship and molecular dynamics simulation

<p>Current research has shown cell-penetrating peptides and antimicrobial peptides (AMPs) as probable vectors for use in drug delivery and as novel antibiotics. It has been reported that the higher the therapeutic index (TI) the higher would be the bacterial cell penetrating ability. To the best of our knowledge, no in-silico study has been performed to determine bacterial cell specificity of the antimicrobial cell penetrating peptides (aCPP’s) based on their TI. The aim of this study was to develop a quantitative structure activity relationship (QSAR) model, which can estimate antimicrobial potential and cell-penetrating ability of aCPPs against <i>S. aureus</i>, to confirm the relationship between the TI and aCPPs and to identify specific descriptors responsible for aCPPs penetrating ability. Molecular dynamics (MD) simulation was also performed to confirm the membrane insertion of the most active aCPPs obtained from the QSAR study. The most appropriate pharmacophore was identified to predict the aCPP’s activity. The statistical results confirmed the validity of the model. The QSAR model was successful in identifying the optimal aCPP with high activity prediction and provided insights into the structural requirements to correlate their TI to cell penetrating ability. MD simulation of the best aCPP with 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC) bilayer confirmed its interaction with the membrane and the C-terminal residues of the aCPP played a key role in membrane penetration. The strategy of combining QSAR and molecular dynamics, allowed for optimal estimation of ligand-target interaction and confirmed the importance of Trp and Lys in interacting with the POPC bilayer.</p> <p>Communicated by Ramaswamy H. Sarma</p