Novel spirooxindole compounds as anticancer agents: targeting Plk4 kinase through design, synthesis, and molecular docking

Plk4 plays a crucial role in controlling the duplication of centrioles and initiating the creation of centrosomes. Disruption of Plk4 leads to aneuploidy and chromosome instability, contributing to aggressive cancers, as well as microcephaly and fatal ciliopathies in children. To effectively treat cancer, it is essential to develop potent Plk4 kinase inhibitors, which are promising anticancer agents due to their ability to induce cancer cell death and selectively target centrosome amplification. This paper examines the molecular design tools and efficient synthesis of novel spirooxindole compounds with anticancer properties, potentially mediated by Plk4 kinase suppression and consequent centrosome reduction. A potential anticancer mechanism was investigated by docking the most effective spirooxindoles into the Plk4 kinase ATPase binding site (PDB code: 4JXF, resolution: 2.40 Å). Compounds 4b and 4i showed the highest inhibition against the Caco2 and HCT116 cell lines, with IC₅₀ values of 68 and 63 µM and 55 and 51 µM, respectively. Their LibDock scores were 110.12 and 109.1, suggesting that their anticancer activity may result from Plk4 enzyme inhibition. Notably, these compounds exhibited a high safety margin, with fibroblast cell line inhibition above 1000 µM. In conclusion, these findings support the potential of spirooxindole derivatives as selective and safe Plk4 inhibitors, offering a promising avenue for targeted cancer therapy with minimal toxicity to normal cells. Graphical abstract

Repurposing FDA-approved drugs against the “main protease” pivotal enzyme in COVID-19 virus using computer-aided drug design techniques

Abstract Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is considered an unprecedented global pandemic in the modern era, infecting millions of people with an approximately 2% death rate. It emerged in late 2019 and researchers worldwide race time to identify druggable targets where medicinal chemists can design potential inhibitors. Objective: Drug repurposing is one of the most convenient methods available now to find already approved drugs for human use with a potential tendency to cure COVID-19. Method: Within this work, the FDA-approved drug database containing 1281 drugs was employed to extract possible drugs that could have activity against the “main protease” enzyme in this virus. Various computer-aided drug design techniques, such as pharmacophore generation, ligand pharmacophore mapping, molecular docking and filtering techniques, were used to identify potential inhibitors. The cocrystallized ligand inside the main protease enzyme was utilized to generate two structure-based pharmacophores that were used as templates for deletion in the FDA database. To validate the selection of the active hits from pharmacophore mapping, molecular docking via “LibDock” was performed, while the highest scoring candidate was selected. Results: Interestingly, three antiviral drugs (lopinavir, saquinavir and remdesivir) were qualified to be potential main protease inhibitors. Conclusion: The researchers in this work recommend clinically investigating the possibility of these drugs as preliminary therapies until selective drugs for COVID-19 virus are approved.</jats:p

Elaboration of Novel TTK1 Inhibitory Leads via QSAR-Guided Selection of Crystallographic Pharmacophores Followed By In Vitro Assay

Introduction: Tyrosine threonine kinase (TTK1) is a key regulator of chromosome segregation. Recently, TTK targeting came into focus for the enhancement of possible anticancer therapies. Objective: In this regard, we employed our well-known method of QSAR-guided selection of the best crystallographic pharmacophore(s) to discover considerable binding interactions that transfer inhibitors into TTK1 binding site. Methods: Sixty-one TTK1 crystallographic complexes were used to extract 315 pharmacophore hypotheses. QSAR modeling was subsequently used to choose a single crystallographic pharmacophore that, when combined with other physicochemical descriptors, elucidates discrepancy in bioactivity of 55 miscellaneous inhibitors. Results: The best QSAR model was robust and predictive (r2(55) = 0.75, r2LOO = 0.72 , r2press against external testing list of 12 compounds = 0.67), Standard error of estimate (training set) (S)= 0.63 , Standard error of estimate (testing set)(Stest) = 0.62. The resulting pharmacophore and QSAR models were used to scan the National Cancer Institute (NCI) database for new TTK1 inhibitors. Conclusion: Five hits confirmed significant TTK1 inhibitory profiles with IC50 values ranging between 11.7 and 76.6 mM. </jats:sec

Ligand Based Pharmacophore Modeling Followed by Biological Screening Lead to Discovery of Novel PDK1 Inhibitors as Anticancer Agents

Background: Phosphoinositide-Dependent Kinase-1 (PDK1) is a serine/threonine kinase, which belongs to AGC kinase family required by cancer cells. Methods: harmacophoric space of 86 PDK1 inhibitors using six diverse sets of inhibitors was explored to identify high-quality pharmacophores. The best combination of pharmacophoric models and physicochemical descriptors was selected by genetic algorithm-based QSAR analysis that can elucidate the variation of bioactivity within the training inhibitors. Two successful orthogonal pharmacophores emerged in the optimum QSAR equation (r2 69 = 0.90, r2 LOO= 0.86, F= 51.92, r2 PRESS against 17 test inhibitors = 0.79). Receiver Operating Characteristic (ROC) curve analyses were used to estimate the QSAR-selected pharmacophores. Results: 5 out of 11 compounds tested had shown potential intracellular PDK1 inhibition with the highest inhibition percent for compounds 92 and 93 as follows; 90 and 92% PDK1 inhibition, respectively. Conclusion: PDK1 inhibitors are potential anticancer agents that can be discovered by combination method of ligand based design with QSAR and ROC analysis. </jats:sec

Identification of the First “Two Digit Nano-molar” Inhibitors of the Human Glyoxalase-I Enzyme as Potential Anticancer Agents

Background: Glyoxalase-I (Glo-I) enzyme is recognized as an indispensable druggable target in cancer treatment. Its inhibition will lead to the accumulation of toxic aldehyde metabolites and cell death. Paramount efforts were spent to discover potential competitive inhibitors to eradicate cancer. Objective: Based on our previously work on this target for discovering potent inhibitors of this enzyme, herein, we address the discovery of the most potent Glo-I inhibitors reported in literature with two digits nano-molar activity. Methods: Molecular docking and in vitro assay were performed to discover these inhibitors and explore the active site's binding pattern. A detailed SAR scheme was generated, which identifies the significant functionalities responsible for the observed activity. Results: Compound 1 with an IC50 of 16.5 nM exhibited the highest activity, catechol moiety as an essential zinc chelating functionality. It has been shown by using molecular modeling techniques that the catechol moiety is responsible for the chelation zinc atom at the active site, an essential feature for enzyme inhibition. Conclusion: Catechol derivatives are successful zinc chelators in the Glo-I enzyme while showing exceptional activity against the enzyme to the nanomolar level. </jats:sec