Chemical Reactivity Properties, Drug-Likeness Features and Bioactivity Scores of the Cholecystokinin Peptide Hormone

Five density functionals, CAM-B3LYP, LC-ωPBE, MN12SX, N12SX and ωB97XD, in connection with the Def2TZVP basis set were assessed together with the SMD solvation model for the calculation of the molecular and chemical reactivity properties of the Cholecystokinin peptide hormone (CCK-8) in the presence of water. All the chemical reactivity descriptors for the systems were calculated via Conceptual Density Functional Theory (CDFT). The potential bioavailability and druggability as well as the bioactivity scoresfor CCK-8 were predicted through different methodologies already reported in the literature which have been previously validated during the study of different peptidic systems. The conclusion was that the CCK-8 peptide will be moderately bioactive regarding all the interactions.

Estimated Binding Energies of Drug-Like and Nondrug-Like Molecules in the Active Site of HIV-1 Integrase, 1BIS.pdb, and Two Mutant Models: Y143R and N155H

Lipinski’s “Rule of Five” was introduced for predicting oral bioavailability to describe drug-like molecules. For the purpose of this research the rules were used to separate potential inhibitors of HIV-1 integrase (1BIS.pdb) into two groups: drug-like and nondrug-like. If one of Lipinski’s “Rule of Five” was not followed the potential inhibitor was classified as nondrug-like. Thirty molecules were identified from the literature, twenty-four drug-like and six nondrug-like, that were docked into the active site of 1BIS.pdb (considered the non-mutated protein) and two mutant models, Y143R and N155H. These are two of the mutations that have led to increased resistance to HIV-1 integrase drugs such as raltegravir and elvitegravir. The computational software, ICM-Pro (Molsoft L.L.C.), was used to determine the estimated binding energy (EBE) of the drug/protein complex. It was found that the nondrug-like molecules generally had a more negative EBE, that is, tighter binding with 1BIS. pdb, though there were several exceptions in the drug-like group. With the protein mutant model Y143R, the majority of drug-like (58%) and nondrug-like molecules (67%) had tighter binding. However, for the mutant model N155H, there was the same percent (46%) of drug-like molecules with tighter binding with the mutant model as with 1BIS.pdb. The drug-like molecules were used when there was a ≥1 kcal/mole difference between 1BIS.pdb and either of the two mutant models to suggest a pharmacophore with structural characteristics for an HIV-1 integrase inhibitor.

Neuroprotective Effect and Mechanism of Tanreqing Injection on Ischemic Stroke:Insights from Network Pharmacology and in vivo Experiments

Objective To explore the neuroprotective effects and mechanism of Tanreqing Injection(TRQ)on treating ischemic stroke based on network pharmacology and in vivo experimental validation.Methods The chemical compounds of TRQ were retrieved based on published data,with targets retrieved from PubChem,Therapeutic Target Database and DrugBank.Network visualization and analysis were performed using Cytoscape,with protein-protein interaction networks derived from the STRING database.Enrichment analysis was performed using Kyoto Encyclopedia of Genes Genomes pathway and Gene Ontology analysis.In in vivo experiments,the middle cerebral artery occlusion(MCAO)model was used.Infarct volume was determined by 2,3,5-triphenyltetrazolium hydrochloride staining and protein expressions were analyzed by Western blot.Molecular docking was performed to predict ligand-receptor interactions.Results We screened 81 chemical compounds in TRQ and retrieved their therapeutic targets.Of the targets,116 were therapeutic targets for stroke.The enrichment analysis showed that the apelin signaling pathway was a key pathway for ischemic stroke.Furthermore,in in vivo experiment we found that administering with intraperitoneal injection of 2.5 mL/kg TRQ every 6 h could significantly reduce the infarct volume of MCAO rats(P<0.05).In addition,protein levels of the apelin receptor(APJ)/phosphatidylinositol 3-kinase(PI3K)/protein kinase B(AKT)pathway were increased by TRQ(P<0.05).In addition,41 chemical compounds in TRQ could bind to APJ.Conclusions The neuroprotective effect of TRQ may be related to the APJ/PI3K/AKT signaling pathway.However,further studies are needed to confirm the findings.

Scalable direct N-methylation of drug-like amines using 12CO2/13CO2 by simple inorganic base catalysis

With the growing urgency of potential catastrophic climate changes due to anthropogenic CO2 emissions,numerous efforts have been devoted to development of synthetic protocols using CO2 as a building block in organic reactions, but the general applicability to complex drug-like substrates remains a challenge.We develop a general protocol for scalable direct N-methylation of a wide-scope drug-like amines using CO2 and polymethylhydrosiloxane-a nontoxic, aerobically-stable hydrosilane considered as an industrial waste-via simple inorganic base catalysis. A rare application of the Sabatier principle in organic chemistry led to the discovery of cheap, nontoxic K3PO4 as an efficient catalyst. Preparations of a wide-scope drug-like amines with carbon-isotope label were also successfully achieved, enabling direct use of CO2 in studies of drug absorption, distribution, metabolism and excretion.

Semi-quantitatively Predicting the Residence Time of Three Natural Products on Endothelin Receptor A by Peak Profiling Using the Receptor Functionalized Macroporous Silica Gel as Stationary Phase

Drug-receptor interaction analysis has been broadly adopted as a tool for the evaluation of the drug-like property.Nowadays,growing evidence has demonstrated that drug e fficacy and safety are highly related to residence time,which equals the reciprocal of the dissociation rate constant(k_(d))of a drug to its target protein.Using endothelin receptor A(ET_(A)R)as a probe,we immobilized the receptor on the surface of macroporous silica gel through a covalent interaction between the epidermal growth factor tyrosine kinase(EGFR)at the C terminal of ET_(A)R and the covalent inhibitor ibrutinib modified on the gel in a one-step fashion.The a ffinity stationary phase was used to semi-quantitatively determine the residence time of natural products on ET_(A)R and evaluate their drug-like property.The k_(d)values of three specific ligands(bosentan,macitentan,and ambrisentan)to ET_(A)R were determined by nonlinear chromatography,peak profiling and peak_(d)ecay.Compared the data determined in free solution of the three methods,peak profiling is considered as the best-fit method for k_(d)determination.Thus,peak profiling was applied for predicting the residence time of three natural products(ferulic acid,berberine,and palmatine)on ET_(A)R.With the longest residence time of 61.11±3.47 s on ET_(A)R,palmatine was evaluated as the most potent compound,which could be developed as a long-acting lead for the receptor.We demonstrate that the high-performance a ffinity chromatography with immobilized ET_(A)R is an alternative for the semi-quantitative measurement of residence time for the drug-like property evaluation of natural products.