Current Drug Targets - Volume 24, Issue 10, 2023

Some diseases caused by trypanosomatid parasites, like Leishmaniasis, Chagas Disease, and Human African Trypanosomiasis (HTA), are challenging to manage, mainly concerning pharmacological therapy because they are associated with vulnerable populations. Unfortunately, there is a lack of significant investments in the search for new drugs. Therefore, one of the strategies to aid the discovery of new drugs is to identify and inhibit molecular targets essential to the parasite's survival, such as the proteasome, which degrades most proteins in the parasite cells. Our study has presented several proteasome inhibitors with various pharmacophoric cores, and two of them, 5, and 13, have stood out in the clinical phase of treatment for leishmaniasis.

Cancer is a complex disease that develops when abnormal cells divide uncontrollably as a consequence of unregulated cell cycle protein activity. Therefore, the cell cycle is crucial for maintaining homeostasis inside the cells during DNA replication and cell division. The presence of mutations within specific genes can disrupt the equilibrium within cells, ultimately leading to the growth of cancer. CDK20 (Cyclin-Dependent Kinase 20) is recently identified as a major controller of cell cycle checkpoints, which regulate cell growth and proliferation and perform a role in the development of many malignancies. CCRK (Cell-Cycle Related Kinase) has recently been renamed CDK20. Emerging studies proclaimed that the upregulation of CDK20 was identified in cancers of the ovary, brain, colon, stomach, liver, and lung. CDK20 was thought to have Cyclin-dependent activating kinase (CAK) activity for CDK2 when it is complexed with Cyclin H. Furthermore, recent studies revealed that CDK20 is involved in the Wnt, EZH2/NF-B, and KEAP1-NRF2 signaling pathways, all of which are interconnected to cancer formation and proliferation. In addition, the structure of CDK20 was predicted using ColabFold, a powerful software integrating AlphaFold's advanced AI system. The present review focuses on a systematic overview of the current knowledge on CDK20 derived from in vitro and in vivo studies and emphasizes its role in carcinogenesis. The validation comparison of the existing CDK20 AlphaFold structure with the ColabFold was found to be exceptionally fast and accurate in generating reliable models.

Background: Skin aging is a natural process resulting from intrinsic (hormonal and genetic) and extrinsic (environmental) factors. Photoaging occurs due to prolonged exposure of the skin to ultraviolet radiation, accounting for 80% of facial aging. Introduction: Characteristics of aging skin include reduced elasticity, the appearance of fine wrinkles, uneven tone, and dryness. Clinical signs of photoaging involve the presence of deeper wrinkles, rough texture, dyschromia and a greater loss of elasticity compared to chronological aging. Methods: This work reported several scientific articles that used computational techniques, such as molecular docking, molecular dynamics and quantitative structure-activity relationship (QSAR) to identify natural products and their derivatives against skin aging and photoaging. Results: The in silico analyses carried out by the researchers predicted the binding affinity and interactions of the natural products with the targets matrix metalloproteinase-1, matrix metalloproteinase- 3, matrix metalloproteinase-9 and tyrosinase. Furthermore, some studies have reported the stability of the protein-ligand complex and the physicochemical properties of the studied compounds. Finally, this research proposes promising molecules against the targets. Conclusion: Thus, studies like this one are relevant to guide new research related to skin aging and photoaging.

The “serotonin hypothesis of depression” is approximately fifty years old, and in spite of vast literature, the exact role of serotonin in depression pathophysiology is still unclear, as whether a lower serotonin level causes depression or depression causes a reduction in serotonin level has become a tough challenge for researchers to understand the actual involvement of serotonin in depression. Several pre-clinical and clinical studies have illustrated the multi-faceted signalling action of serotonin in depression and vouch for the significant or unavoidable role of serotonin in depression. In this review, the journey of the serotonin hypothesis of depression from the 1950s to the present time has been analysed to understand the serotonin hypothesis of depression and investigate the new molecular targets for the development of new future anti- depressants. The old and new theories of possible cellular mechanisms found to be involved in the pathophysiology of major depression or stress, such as polymorphism of serotonin transporters, enzyme modulating serotonergic activity, reduction in the level of serotonin and involvement of different sub-types of receptors, have been discussed in the respective review. Thus, in this review, the new signature targets to increase serotonin levels have been identified, which would help the researcher in the drug development of new faster-acting antidepressants.

Background: Human African trypanosomiasis (HAT) is a parasitic infection that may lead to death if left untreated. This disease is caused by a protozoan parasite of the genus Trypanosoma and is transmitted to humans through tsetse fly bites. The disease is widespread across Sub- -Saharan Africa, with 70% of cases in recent reports in the Democratic Republic of the Congo and an average of less than 1000 cases are declared annually. Since there is no appropriate treatment for HAT, steroidal and triterpenoid saponins have been reported to be effective in in vitro studies and might serve as scaffolds for the discovery of new treatments against this disease. Aim of the Study: The present study aimed to summarize up-to-date information on the anti-Trypanosoma brucei activity of steroidal and triterpenoid saponins. The mechanisms of action of in vitro bioactive compounds were also discussed. Methods: Information on the anti-Trypanosoma brucei activity of plant saponins was obtained from published articles, dissertations, theses, and textbooks through a variety of libraries and electronic databases. Results: There has been incredible progress in the identification of steroidal and triterpenoid saponins with pronounced in vitro activity against Trypanosoma brucei. Indeed, more than forty saponins were identified as having anti-T. brucei effect with activity ranging from moderate to highly active. The mechanisms of action of most of these saponins included DNA damage, cell cycle arrest, induction of apoptosis through downregulation of bcl-2 and MDM2, and upregulation of Bax and Bak, among others. Conclusion: Referring to in vitro studies, plant saponins have shown anti-Trypanosoma brucei activity; however, more cytotoxic and in vivo studies and detailed mechanisms of action of the bioactive saponins should be further considered.