With an alarming increase in the number of cancer patients and a variety of tumors, it is high time for intensive investigation on more efficient and potent anti-tumor agents. Though numerous agents have enriched the literature, still there exist challenges, with the availability of different targets and possible cross-reactivity. Herein we have chosen the phosphoinositide 3-kinase (PI3K) as the target of interest and investigated the potential of pyrido fused imidazo[4,5-c]quinoline derivatives to bind strongly to the active site, thereby inhibiting the progression of various types of tumors. The AutoDock, Glide and the Prime-MM/GBSA analysis are used to execute the molecular docking investigation and validation for the designed compounds. The anti-tumor property evaluations were carried out by using PASS algorithm. Based on the GLIDE score, the binding affinity of the designed molecules towards the target PI3K was evaluated. The energetics associated with static interactions revealed 1j as the most potential candidate and the dynamic investigations including RMSD, RMSF, Rg, SASA and hydrogen bonding also supported the same through relative stabilization induced through ligand interactions. Subsequently, the binding free energy of the Wortmannin and 1j complex calculated using MM-PBSA analysis. Further evaluations with PASS prediction algorithm also supported the above results. The studies reveal that there is evidence for considering appropriate pyrido fused imidazo[4,5-c]quinoline compounds as potential anti-tumor agents.

Two mutant strains of Amycolatopsis mediterranei VA17 and VA18 were isolated using physical (UV) and chemical (NTG) mutagens gave high rifamycin B than the parent type when grown in the same fermentation medium with a pH of 7.2, temperature 32°C for a period of 12 days. The cultural conditions of both mutant strains are similar to the parent strain except temperature which was higher by 4°C. By this mutation and selection study, rifamycin B production was improved from 1400 mg/l to 2450 mg/l.

Neomorphic transformations in isocitrate dehydrogenase 1 (IDH1) are the key mutations prevalently found in various cancers including glioma. Recently identified mIDH1 specific inhibitors showed modest brain penetrating potential and dose-limiting toxicity. Herein, we elucidate virtual screening strategies to discover persuasive mIDH1 inhibitors from the approved subset of the DrugBank database consisting of 2715 molecules. Initially, a structural similarity search identified a total of 1432 lead molecules. The resultant compounds were inspected by molecular docking along with MM-GBSA and ADMET analyses. Altogether, the analyses identified Abemaciclib as the hit against mIDH1. Notably, abemaciclib was able to form hydrogen bond interaction with active site residues of mIDH1 protein. In the end, the dynamic behavior of the hit complex was also examined using molecular dynamics simulation studies. The outcome of the study culminates that the hit complex was stable throughout the simulation period of 100[Formula: see text]ns. It is worth noting that benzimidazole moiety of abemaciclib was reported to show inhibitory activity against glioma cells. Overall, these findings highlight that abemaciclib has the potential as a lead molecule against glioma. Indeed, the screened hit compound could be further explored for the development of mIDH1 inhibitor with great brain penetrating ability and low toxicity.

No abstract

Neomorphic transformation in isocitrate dehydrogenase 1 (IDH1) are the key mutations prevalently found in various cancers including glioma. Recently identified mIDH1 specific inhibitors such as ivosidenib and Vorasidenib were restricted for use due to its modest brain penetrating potential and dose limiting toxicity respectively. Herein, we elucidate integrated virtual screening strategies to discover persuasive mIDH1 inhibitors from the approved subset of the DrugBank database consisting of 2715 molecules. Initially, structural similarity search identified a total of 1432 lead molecules. The resultant compounds were inspected by molecular docking along with MM-GBSA and ADMET analyses. Altogether, the analyses identified DB12001 (Abemaciclib) as the hit against mIDH1. Notably, Abemaciclib was able to form hydrogen bond interaction with active site residues of mIDH1 protein. In the end, the dynamic behavior of the hit complex was also examined using molecular dynamic (MD) simulation studies. The outcome of the study culminates that the hit complex was stable throughout the simulation period of 100ns. It is worth noting that benzimidazole moiety of Abemaciclib was reported to show inhibitory activity against glioma cells. Overall, these findings highlight that DB12001 has the potential as lead molecule against glioma. Indeed the screened hit compound could be further explored for the development of mIDH1 inhibitor with great brain penetrating ability and low toxicity.