Intorduction: Nowadays cancer has become a challenging threat for the public health, and causing various financial, economical, mental, and physiological problems. Chemotherapy is still going through the struggle in subduing and curing the cancer due to the adverse drug reactions and unwanted complications.
Hence there is an emergence for finding new targets and developing a more specific antineoplastic compounds. A disruption in cell proliferation, if not corrected, may lead to cancer. Cyclin-Dependent Kinases (CDKs) perform a crucial role in cell cycle and proliferation. A malfunction in performance of CDKs is a well- known cause of cancer, Therefore this enzyme family could be a reliable target for development of anti-neoplastic pharmaceuticals.
A new approach for designing new compounds is virtual in-silico studies, such as molecular dynamics, molecular docking, high throughout virtual screening, and QSAR. In this study we designed a potential CDK2/CyclinE1 inhibitor using virtual studies. The most desirable compound was synthesized and the potency of the compound was predicted using 2D-QSAR models. The Ligand Receptor complex reactions where investigated using DESMOND molecular dynamics for better prediction and understanding.
Methods and Material: Using previous studies a set of compounds were selected and their binding affinity to CDK2/CyclinE1 was investigated using Maestro Molecular Modeling Interface by Docking and Molecular dynamic simulations, (PDB ID: 5L2W) for MD simulation the complex was monitored at each 50 nsec with the temperature of 300K and the pressure of 1.01325 Bar. The potential compounds where synthesized using amidation and amination routes. 2D-QSAR model for this enzyme was designed using Fingerprint 2D-QSAR, Maestro Molecular Modeling Interface with two compound groups (Test and Training). the potency of every chosen compounds used in this modeling where in the range of μM. The fingerprint 2D-QSAR modeling led to a model suitable for IC50 prediction.
Results: through the virtual screenings the phthalimide core compounds were identified as potential CDK2/CyclinE1 inhibitors. DM investigations showed that during 50 nsecs of interaction, the designed compound made over 100% contacts (1.34 contact). Docking score of the designed compounds where within in the range of (-9 to -11 kcal/mol) and therefore the potent component were synthesized and purified (Yield = 71%). the compound “2-((6-aminopyridin-2-yl)amino)-N-(N-(1,3-dioxoisoindolin-2-yl)carbamimidoyl)acetamide” showed the highest affinity towards the receptor complex. Based on calculated and refined 2D-QSAR model (linear method, R2= 0, 9315, SD = ±0.03) The IC50 of the designed compounds were predicted to be within the range of 0.9-1.7 μM.
Key words: Synthesis , Molecular Dynamics, Molecular Design, Cyclin-Dependent kinase, Cancer.
: Bramson, H.N., Corona, J., Davis, S.T., Dickerson, S.H., Edelstein, M., Frye, S.V., Gampe, R.T., Harris, P.A., Hassell, A., Holmes, W.D. and Hunter, R.N., 2001. Oxindole-based inhibitors of cyclin-dependent kinase 2 (CDK2): design, synthesis, enzymatic activities, and X-ray crystallographic analysis. Journal of medicinal chemistry, 44(25), pp.4339-4358.
: Kumar, A., Rai, S., Rathi, E., Agarwal, P. and Kini, S.G., 2021. Pharmacophore-guided fragment-based design of novel mammalian target of rapamycin inhibitors: extra precision docking, fingerprint-based 2D and atom-based 3D-QSAR modelling. Journal of Biomolecular Structure and Dynamics, 39(4), pp.1155-1173.
: Tutone, M. and Almerico, A.M., 2017. Recent advances on CDK inhibitors: An insight by means of in silico methods. European journal o