This review aims to present a comprehensive state-of-the-art analysis of the bidirectional crosstalk between gut microbiota and the central nervous system (CNS). The literature concerning the potential effects of gut microbiota on psychiatric disorders through neural pathways comprising the ‘gut-brain axis’ were gathered. In addition, the influence of probiotics and prebiotics and dairy-rich diets combined with the intake of probiotics and prebiotics on gut microbiota and the subsequent relationship with brain function was reviewed. However, a meta-analysis on the effectiveness of probiotic supplementation in psychiatric disorders is lacking. Therefore, a systematic search of PubMed, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov databases from January 1969 to December 2019 was conducted. It led to the identification of a total of 844 research articles. Of these, a total of 23 studies met the meta-analysis criteria. Statistical analysis revealed that there was no significant difference in the symptoms of schizophrenia, stress, and anxiety between probiotic and placebo groups, post-intervention. Probiotic administration reduced depressive symptoms among patients with depression in a statistically significant manner (standardised mean difference (SMD) = -0.87; 95% confidence interval (95% confidence interval): -1.66, -0.99; P=0.03). Further evidence from larger and more rigorous studies with longer duration of probiotic administration, as well as well-defined populations, homogenous probiotic intervention and outcome measures, are needed to clarify the potential therapeutic effects of probiotics on psychiatric symptoms. Based on the current literature, it seems that not all probiotic-/prebiotic-/dairy-rich diet-based treatments exhibited a psychobiotic effect on the CNS. Among the parameters determining the success of the given treatment, the most significant were probiotic composition (multi-strain formulation), the quantity of ingested psychobiotics and the duration of the study.

The main protease (Mpro) of SARS-CoV-2 is an essential enzyme that plays a critical part in the virus’s life cycle, making it a significant target for developing antiviral drugs. The inhibition of SARS-CoV-2 Mpro has emerged as a promising approach for developing therapeutic agents to treat COVID-19. This review explores the structure of the Mpro protein and analyzes the progress made in understanding protein–ligand interactions of Mpro inhibitors. It focuses on binding kinetics, origin, and the chemical structure of these inhibitors. The review provides an in-depth analysis of recent clinical trials involving covalent and non-covalent inhibitors and emerging dual inhibitors targeting SARS-CoV-2 Mpro. By integrating findings from the literature and ongoing clinical trials, this review captures the current state of research into Mpro inhibitors, offering a comprehensive understanding of challenges and directions in their future development as anti-coronavirus agents. This information provides new insights and inspiration for medicinal chemists, paving the way for developing more effective Mpro inhibitors as novel COVID-19 therapies.

Background: The phosphodiesterase 10 (PDE10) family, identified in 1999, is mainly expressed in the brain, particularly in the striatum, within the medium spiny neurons, nucleus accumbens, and olfactory tubercle. Inhibitors of PDE10 (PDE10-Is) are a conceptually rational subject for medicinal chemistry with potential use in the treatment of psychiatric and neurodegenerative diseases. Objective: This review is based on peer-reviewed published articles, and summarizes the cellular and molecular biology of PDE10 as a rational target for psychiatric and neurodegenerative drug discovery. Here, we present the classification of PDE10-Is from a medicinal chemistry point of view across a wide range of different, drug-like chemotypes starting from theophylline and caffeine analogs, papaverine and dimethoxy catechol type PDE10-Is, TP-10, MP-10, MP-10/papaverine/quinazoline series inhibitors, and ending with the newest inhibitors obtained from fragment-based lead discovery (FBLD). The authors have collated recent research on inhibition of PDE10A as a promising therapeutic strategy for psychiatric and neurodegenerative diseases, based on its efficacy in animal models of schizophrenia, Parkinson’s, Huntington’s, and Alzheimer’s diseases. This review also presents pharmacological data on PDE10-Is as possible therapeutics for the treatment of cognitive deficits, obesity and depression. Moreover, it summarizes the current strategies for PDE10-Is drug discovery based on the results of clinical trials. The authors also present the latest studies on crystal structures of PDE10 complexes with novel inhibitors.

Despite tremendous research efforts at every level, globally, there is still a lack of effective drugs for the treatment of Alzheimer′s disease (AD). The biochemical mechanisms of this devastating neurodegenerative disease are not yet clearly understood. This review analyses the relevance of multiple ligands in drug discovery for AD as a versatile toolbox for a polypharmacological approach to AD. Herein, we highlight major targets associated with AD, ranging from acetylcholine esterase (AChE), beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1), glycogen synthase kinase 3 beta (GSK-3β), N-methyl-d-aspartate (NMDA) receptor, monoamine oxidases (MAOs), metal ions in the brain, 5-hydroxytryptamine (5-HT) receptors, the third subtype of histamine receptor (H₃ receptor), to phosphodiesterases (PDEs), along with a summary of their respective relationship to the disease network. In addition, a multitarget strategy for AD is presented, based on reported milestones in this area and the recent progress that has been achieved with multitargeted-directed ligands (MTDLs). Finally, the latest publications referencing the enlarged panel of new biological targets for AD related to the microglia are highlighted. However, the question of how to find meaningful combinations of targets for an MTDLs approach remains unanswered.