Structure-based De Novo Design and Docking Studies of 5(S)-Methyl-L-Proline Containing Peptidomimetic Compounds as Dipeptidyl Peptidase-4 Inhibitors.

BACKGROUND: Diabetes affects millions of people worldwide, with predicted numbers of about 700 million adults affected by 2045. Among the several anti-diabetic drug therapies available in the market, Dipeptidyl Peptidase-4 (DPP-4) inhibitors have emerged as a promising therapeutic approach with scope for exploration in the segment of peptidomimetics. OBJECTIVE: Series of proline-containing peptidomimetic compounds were designed and investigated for their drug-likeness through Lipinski's rule of five, lead-likeness through the rule of three, predictive pharmacokinetic studies (absorption, distribution, metabolism, and excretion), and toxicity properties through in-silico approaches. The designed compounds were evaluated for their interactions with binding sites of the enzyme DPP-4 using an extra precision docking approach. METHODS: Proline-containing peptidomimetic compounds were designed rationally. Drug-likeness and lead-likeness properties were calculated using Schrödinger Maestro v11.2 software. ADME and toxicity properties were predicted using PreADMET version 2.0. Docking study was performed using Schrödinger Maestro v11.2 software, and ligands for the study were designed using MarvinSketch software. RESULTS: 5(S)-methyl-L-proline containing 17 ligands were designed. All of them were found to obey Lipinski's rule of five. Compounds were found to have good ADME profile and low toxicity predictions. CONCLUSION: Four compounds were found to have good interactions with DPP-4 binding sites and hence created the scope to develop DPP-4 inhibitors containing 5(S)-methyl-L-proline moiety.

Improvement of physicochemical parameters of acyclovir using cocrystallization approach

ABSTRACT Acyclovir is an antiviral drug having potent activity against the virus of herpes family and varicella zoster. Unfortunately, drug suffers very poor oral bioavailability (15-30%). The main objective of present study was to develop acyclovir cocrystals with improved solubility which may result in improvement of bioavailability. Hansen solubility approach was used as a tool to predict the cocrystal formation of a drug with selected coformer. Cocrystals of acyclovir with various coformers were screened in order to enhance their water solubility. Cocrystals of the drug were prepared using various methods like solvent evaporation, wet grinding, and antisolvent addition. Formation of cocrystals by solvent evaporation method was found to be better method amongst all. Optimization of cocrystal formation was carried out by employing different solvents as well as the stoichiometric ratio of acyclovir with that of coformer. Synthesis of cocrystals was optimized using water as a solvent system resulted in good agreements. The potential cocrystal formation of acyclovir was characterized by IR, PXRD and DSC techniques. An in-vitro dissolution study was performed to determine the dissolution rate of cocrystals. The results suggest that acyclovir forms cocrystals with tartaric acid and the initial dissolution rate of synthesized cocrystals were considerably faster as compared to pure acyclovir.