Multi-targeted drug design strategies for the treatment of schizophrenia.

INTRODUCTION: Schizophrenia is a complex psychiatric disease (or a conglomeration of disorders) manifesting with positive, negative and cognitive symptoms. The pathophysiology of schizophrenia is not completely known; however, it involves many neurotransmitters and their receptors. In order to treat schizophrenia, drugs need to be multi-target drugs. Indeed, the action of second and third generation antipsychotics involves interactions with many receptors, belonging mainly to aminergic GPCRs. AREAS COVERED: In this review, the authors summarize current concepts of schizophrenia with the emphasis on the modern dopaminergic, serotoninergic, and glutamatergic hypotheses. Next, they discuss treatments of the disease, stressing multi-target antipsychotics. They cover different aspects of design of multi-target ligands, including the application of molecular modeling approaches for the design and benefits and limitations of multifunctional compounds. Finally, they present successful case studies of multi-target drug design against schizophrenia. EXPERT OPINION: Treatment of schizophrenia requires the application of multi-target drugs. While designing single target drugs is relatively easy, designing multifunctional compounds is a challenge due to the necessity to balance the affinity to many targets, while avoiding promiscuity and the problems with drug-likeness. Multi-target drugs bring many benefits: better efficiency, fewer adverse effects, and drug-drug interactions and better patient compliance to drug regime.

Thyroid Peroxidase Activity is Inhibited by Phenolic Compounds-Impact of Interaction.

The aim of this study was to estimate the mode of thyroid peroxidase (TPO) inhibition by polyphenols: Chlorogenic acid, rosmarinic acid, quercetin, and rutin. All the tested polyphenols inhibited TPO; the IC50 values ranged from 0.004 mM to 1.44 mM (for rosmarinic acid and rutin, respectively). All these pure phytochemical substances exhibited different modes of TPO inhibition. Rutin and rosmarinic acid showed competitive, quercetin-uncompetitive and chlorogenic acid-noncompetitive inhibition effect on TPO. Homology modeling was used to gain insight into the 3D structure of TPO and molecular docking was applied to study the interactions of the inhibitors with their target at the molecular level. Moreover, the type and strength of mutual interactions between the inhibitors (expressed as the combination index, CI) were analyzed. Slight synergism, antagonism, and moderate antagonism were found in the case of the combined addition of the pure polyphenols. Rutin and quercetin as well as rutin and rosmarinic acid acted additively (CI = 0.096 and 1.06, respectively), while rutin and chlorogenic acid demonstrated slight synergism (CI = 0.88) and rosmarinic acid with quercetin and rosmarinic acid with chlorogenic acid showed moderate antagonism (CI = 1.45 and 1.25, respectively). The mixture of chlorogenic acid and quercetin demonstrated antagonism (CI = 1.79). All the polyphenols showed in vitro antiradical ability against 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid), ABTS. The highest ability (expressed as IC50) was exhibited by rosmarinic acid (0.12 mM) and the lowest value was ascribed to quercetin (0.45 mM).