article · Journal of Biomolecular Structure and Dynamics
This study explored the quantitative structure-activity relationships of thiazole derivatives acting as potential anticancer agents against hepatocellular carcinoma. Using density functional theory to calculate electronic descriptors alongside multiple linear regression, a predictive computational model was established. Key molecular features influencing anticancer activity included orbital energy, electronic energy, shape coefficient, number of rotatable bonds, and index of refraction. Applying this validated model, new thiazole derivatives were designed and assessed for their pharmacokinetic and activity profiles. These novel compounds were further evaluated through molecular docking and one hundred nanosecond molecular dynamics simulations to determine their binding stability and affinity towards cyclin-dependent kinase 2, a target protein. The computational investigations identified four promising candidate inhibitors, designated A1, A3, A5, and A6. Among these, compound A5 demonstrated notable stability within the active binding site of the target protein.
Hepatocellular carcinoma remains a severe form of cancer requiring effective new therapeutic agents. By using computational modelling to establish how specific chemical properties influence anticancer activity, drug discovery researchers can design candidate molecules more efficiently before undertaking physical synthesis. Demonstrating the binding stability of these newly designed thiazole compounds against cyclin-dependent kinase 2 provides clear starting points for further therapeutic development.
This research provides computational lead candidates for pharmaceutical developers focused on hepatocellular carcinoma therapeutics. It identifies four specific thiazole molecules with favourable predicted pharmacokinetics, especially compound A5. Because the evidence is derived exclusively from in silico modelling, docking, and molecular dynamics simulations, the technology remains at an early concept stage. It would require physical chemical synthesis, in vitro validation, and extensive preclinical testing before attracting licensing or commercial drug pipeline investment.
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The present study aims to investigate about the quantitative structure-activity relationship (QSAR) of a series of Thiazole derivatives reported as anticancer agents (hepatocellular carcinoma), using principally the electronic descriptors calculated by the DFT method and by applying the multiple linear regression method. The developed model showed good statistical parameters (R2 = 0.725, R2adj = 0.653, MSE = 0.060, R2test = 0.827, Q2cv = 0.536). The energy EHOMO orbital, electronic energy (TE), shape coefficient (I), number of rotatable bonds (NROT), and index of refraction (n) were revealed to be the main descriptors influencing the anti-cancer activity. Further, new Thiazole derivatives have been designed and their activities and pharmacokinetic properties have been predicted using the validated QSAR model. The designed molecules were then assessed to molecular docking (MD), and molecular dynamic (MDs) simulation accompanied by the calculation of the binding affinity using MMPBSA script according to 100 ns a simulation trajectory, to study both their affinity and their stability towards CDK2 as a target protein for the cancer disease treatment. This research concluded with the identification of four new CDK2 inhibitors which are A1, A3, A5, and A6 showing good pharmacokinetic properties. The MDs results revealed that the newly designed compound A5 remained stable in the active center of the discovered CDK2 protein, indicating its potential as a novel inhibitor for the treatment of hepatocellular carcinoma. The current findings may eventually contribute to the development of robust CDK2 inhibitors in the future.Communicated by Ramaswamy H. Sarma
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DOI: 10.1080/07391102.2023.2212304
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