Current Medicinal Chemistry - Volume 30, Issue 32, 2023

Cocaine, also known as methyl benzoylecgonine, is one of the most used drugs of abuse and one of the oldest; however, there has been a recent increase in the consumption of this substance. This trend has once again caught the attention of the scientific community. We discuss the current knowledge about this drug, focusing our attention on the forensic approach. Despite the fact that the cut-off of positivity to cocaine in drug tests is quite high, most current tests are able to detect much lower concentrations and could improve forensic sciences in both post-mortem investigations and in people screening. Immunological assays possessing substantial cross-reactivity to cocaine are particularly useful for screening oral fluid, hair, and post-mortem blood, where significant concentrations of the drug can be found. Liquid chromatography has now supplanted the previous techniques because it is very sensitive and specific and allows samples to be analyzed in a shorter time with only minimal sample preparation. Recent studies have focused on increased sensitivity, reduced processing times, and cheaper analysis.

Objective: The purpose of this article is to describe the state-of-art of neuroanatomical and cellular aspects of the cerebellum in epilepsy. Background: Over the years, cerebellum epileptogenesis has been widely studied. There is growing evidence linking the cerebellum with this pathology by several other structures involved: mainly the limbic system, thalamus, cerebral cortex, red nucleus, and reticular formation. As a result, these anatomical and cellular changes in the cerebellum might trigger the genesis and propagation of seizures. Discussion: We herewith outline the cerebellum's deep nuclei physiological pathways, responsible for seizure spread via ion channels and neurotransmitter dysfunction. Additionally, we describe the shifts in seizures produced after cell death, gene expression, and protein interaction with their respective molecular and anatomical pathways. Conclusion: Finally, we highlight the role played by the cerebellum in seizure propagation to the brain and how it can be counteracted in some subtypes of drug-resistant epilepsy.

The prevalence of obesity and its associated diseases has increased dramatically, and they are major threats to human health worldwide. A variety of approaches, such as physical training and drug therapy, can be used to reduce weight and reverse associated diseases; however, the efficacy and the prognosis are often unsatisfactory. It has been reported that natural food-based small molecules can prevent obesity and its associated diseases. Among them, alkaloids and polyphenols have been demonstrated to regulate lipid metabolism by enhancing energy metabolism, promoting lipid phagocytosis, inhibiting adipocyte proliferation and differentiation, and enhancing the intestinal microbial community to alleviate obesity. This review summarizes the regulatory mechanisms and metabolic pathways of these natural small molecules and reveals that the binding targets of most of these molecules are still undefined, which limits the study of their regulatory mechanisms and prevents their further application. In this review, we describe the use of Discovery Studio for the reverse docking of related small molecules and provide new insights for target protein prediction, scaffold hopping, and mechanistic studies in the future. These studies will provide a theoretical basis for the modernization of anti-obesity drugs and promote the discovery of novel drugs.

Discovery of MDM2 and MDM2-p53 interaction inhibitors changed the direction of anticancer research as it is involved in about 50% of cancer cases globally. Not only the inhibition of MDM2 but also its interaction with p53 proved to be an effective strategy in anticancer drug design and development. Various molecules of natural as well as synthetic origin have been reported to possess excellent MDM2 inhibitory potential. The present review discusses the pathophysiology of the MDM2-p53 interaction loop and MDM2/MDM2-p53 interaction inhibitors from literature covering recent patents. Focus has also been put on characteristic features of the active site of the target and its desired interactions with the currently FDA-approved inhibitor. The designing approach of previously reported MDM2/MDM2-p53 interaction inhibitors, their SAR studies, in silico studies, and the biological efficacy of various inhibitors from natural as well as synthetic origins are also elaborated. An attempt is made to cover recently patented MDM2/MDM2- p53 interaction inhibitors.

Background: Statins are the main lipid-lowering drugs and are used in the prevention of cardiovascular diseases (CVDs). Since the results have been, to some extent, inconsistent in the clinical trials concerning different types of CVDs, a systematic review and meta-analysis was performed to prove the effect of statins on decreasing elevated levels of total cholesterol, triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) in patients with CVDs. Methods: Literature search was performed on major electronic databases (MEDLINE/ PubMed, Scopus, and ISI Web of Science) from inception up to July 2021 to find randomized controlled trials (RCTs) evaluating the effect of different statins on different types of CVDs. The effect size was determined using weighted mean difference (WMD) and corresponding 95% confidence interval (CI). Results: Statin therapy significantly decreased levels of total cholesterol (WMD = -33.37 mg/dl, 95% CI: -45.98 to -20.76, P<0.001), LDL-C (WMD = -29.42 mg/dl, 95% CI: -36.81 to -22.03, P<0.001), and TG (WMD = -15.19 mg/dl, 95% CI = -26.41 to -3.97, P<0.001), and increased levels of HDL-C (WMD = 1.55 mg/dl, 95% CI: 0.20, to 2.90, P=0.02) in patients with different CVDs. Conclusion: Statin therapy was found effective in lowering levels of total cholesterol, LDL-C, and TG, and increasing levels of HDL-C in patients with different CVDs.