Molecular Docking and ADME Study of Quinoline and Chalcone based Derivatives for Anti-Cancer Activity

Cancer is a big issue that affects people all over the world. It develops as a result of uncontrolled cell growth. The interaction between developed ligands and thymine phosphorylation was investigated in this study, which was computationally optimized. The aim of this study was to examine the anticancerous activity of designed ligands in thymine phosphorylation (PDB ID: 1UOU) in order to minimize the cost and time required to develop a novel anticancer drug with minimal side effects. All the designed ligands showed mild to excellent binding with proteins. Most of the ligands exhibited better interaction compared to reference compound Tamoxifen with pdb files. Some of the designed ligands among (1-7) in qunoline derivatives and (1-5) in Chalcone derivatives showed excellent docking scores with PDB file (1UOU) of thymine phosphorylation. All the designed ligands and Zinc databases were docked with 1UOU PDB files of protein, and it was found that out of twenty-five designed ligands in Qunoline series, ligand 25 showed the best binding (docking score −8.268) with 1UOU PDB of protein thymine phosphorylation. And that out of ten designed ligands in Chalcone series, ligand K1 showed the best binding (docking score −9.433) with 1UOU PDB of protein thymine phosphorylation. Docked ligand cavity of ligand ku 25 in qunoline series and K 9 in Chalcone series showed important hydrophobic/non-polar residues such as Ile199, Ile316, Trp119, Phe168, Ile198, Cys172, Tyr188, Tyr398, Tyr435, Phe343, Tyr60, Leu328, Leu171, and showed pi-pi interaction with Tyr326. Further wet laboratory studies are continued in our laboratory to confirm and find out the efficiency and activity of target compounds.

Absorption, Metabolism, Distribution, and Excretion of Letermovir

Background: Letermovir is approved for prophylaxis of cytomegalovirus infection and disease in cytomegalovirus-seropositive hematopoietic stem-cell transplant (HSCT) recipients. Objective: HSCT recipients are required to take many drugs concomitantly. The pharmacokinetics, absorption, distribution, metabolism, and excretion of letermovir and its potential to inhibit metabolizing enzymes and transporters In vitro were investigated to inform on the potential for drug‒drug interactions (DDIs). Methods: A combination of in vitro and in vivo studies described the absorption, distribution, metabolism, and routes of elimination of letermovir, as well as the enzymes and transporters involved in these processes. The effect of letermovir to inhibit and induce metabolizing enzymes and transporters were evaluated In vitro and its victim and perpetrator DDI potentials were predicted by applying the regulatory guidance for DDI assessment. Results: Letermovir was a substrate of CYP3A4/5 and UGT1A1/3 in vitro. Letermovir showed concentration-dependent uptake into organic anionic transporting polypeptide (OATP)1B1/3-transfected cells and was a substrate of P-glycoprotein (P-gp). In a human ADME study, letermovir was primarily recovered as unchanged drug and minor amounts of a direct glucuronide in feces. Based on the metabolic pathway profiling of letermovir, there were few oxidative metabolites in human matrix. Letermovir inhibited CYP2B6, CYP2C8, CYP3A, and UGT1A1 in vitro, and induced CYP3A4 and CYP2B6 in hepatocytes. Letermovir also inhibited OATP1B1/3, OATP2B1, OAT3, OCT2, BCRP, BSEP, and P-gp. Conclusion: The body of work presented in this manuscript informed on the potential for DDIs when letermovir is administered both intravenously and orally in HSCT recipients.