Combination Of Molecular Docking Studies Research Articles

BISPHOSPHONATES-PDA: CORRELATION BETWEEN STRUCTURE AND PHYSICOCHEMICAL PROPERTIES

Bisphosphonates are used to treat a number of bone related diseases such as osteosarcoma, malignant hypercalcemia, osteomyelitis. Developing novel drug delivery systems may overcome the adverse reactions caused by traditional administration. This study uses a combination of molecular docking studies and correlation techniques between structure – physical and chemical properties to assess how different bisphosphonates (alendronate, risedronate, pamidronate, zoledronate) interact with polydopamine in order to later design new formulations. The structure of polydopamine is still under discussion therefore, its bisphosphonate binding properties have not been completely established. Polydopamine was modeled by repeated docking of tetrameric subunits combined in two ways which led to simple and mixed oligomers. Fingerprint descriptors, namely electronegativity of the OMO-UMO quantum molecular states, were used for the correlation studies. The correlation coefficients suggest that several atom species such as nitrogen and carbon have increased contributions to the formation of both HOMO and LUMO molecular states. The results showed that the most stable complex was obtained with risedronate for both simple and mixed dopamine oligomers (-186.00 kJ/mol and -184.92 kJ/mol).

In Vitro and In Silico Analysis of the Residence Time of Serotonin 5-HT7 Receptor Ligands with Arylpiperazine Structure: A Structure-Kinetics Relationship Study.

During the last decade, the kinetics of drug-target interaction has received increasing attention as an important pharmacological parameter in the drug development process. Several studies have suggested that the lipophilicity of a molecule can play an important role. To date, this aspect has been studied for several G protein-coupled receptors (GPCRs) ligands but not for the 5-HT7 receptor (5-HT7R), a GPCR proposed as a valid therapeutic target in neurodevelopmental and neuropsychiatric disorders associated with abnormal neuronal connectivity. In this study, we report on structure-kinetics relationships of a set of arylpiperazine-based 5-HT7R ligands. We found that it is not the overall lipophilicity of the molecule that influences drug-target interaction kinetics but rather the position of polar groups within the molecule. Next, we performed a combination of molecular docking studies and molecular dynamics simulations to gain insights into structure-kinetics relationships. These studies did not suggest specific contact patterns between the ligands and the receptor-binding site as determinants for compounds kinetics. Finally, we compared the abilities of two 5-HT7R agonists with similar receptor-binding affinities and different residence times to stimulate the 5-HT7R-mediated neurite outgrowth in mouse neuronal primary cultures and found that the compounds induced the effect with different timing. This study provides the first insights into the binding kinetics of arylpiperazine-based 5-HT7R ligands that can be helpful to design new 5-HT7R ligands with fine-tuning of the kinetic profile.

Design, synthesis, and local anti-inflammatory activity of 17β-carboxamide derivatives of glucocorticoids.

Molecular docking studies were performed on 18 17β-carboxamide steroids in order to select compounds with potential local anti-inflammatory activity. These derivatives are amides of cortienic acids (obtained from hydrocortisone, prednisolone, and methylprednisolone) with methyl or ethyl esters of six amino acids. Interactions with the glucocorticoid receptor (GR), binding energies and ligand efficiency values of these compounds were compared with dexamethasone and cortienic acid obtained from prednisolone (inactive metabolite). On the basis of molecular docking studies, seven compounds were selected and their binding affinities for the GR were predicted by use of the exponential model created in this study. Subsequently, selected compounds were synthesized in good yields by use of modified N,N'-dicyclohexylcarbodiimide (DCC)/1-hydroxybenzotriazole (HOBt) coupling procedure. Finally, the local anti-inflammatory activity of the synthesized compounds was examined by use of the croton oil-induced ear edema test. In vivo evaluation of systemic side effects as well as in silico prediction of metabolism were performed on the derivative with the best local anti-inflammatory activity. The combination of molecular docking studies and the exponential model for the GR binding affinity prediction could be used as an in silico tool for the rational design of novel 17β-carboxamide steroids with potentially better biological profile than dexamethasone.