Computational modeling of potential milciclib derivatives inhibitor-CDK2 binding through global docking and accelerated molecular dynamics simulations

• Published in: Informatics in medicine unlocked 2022, Vol.33, p.101069, Article 101069
• Main Authors: Khanam, Mushira, Moin, Abu Tayab, Ahmed, Kazi Ahsan, Patil, Rajesh B., Ripon Khalipha, Abul Bashar, Ahmed, Nafisa, Bagchi, Rajat, Ullah, Md Asad, Ferdoush, Jannatul, Islam, Saiful, Rudra, Bashudev
• Format: Article
• Language: English
• Subjects: Anticancer drug; Halogenated derivatives; Hepatocellular carcinoma; Milciclib; Molecular docking; Molecular dynamics simulation; Non-bond interactions
• ISSN: 2352-9148; 2352-9148
• DOI: 10.1016/j.imu.2022.101069

Hepatocellular carcinoma (HCC) is the most common malignant condition of the liver that occurs as a result of uncontrolled cellular proliferation after a series of disruptions at cell cycle regulatory checkpoints in the normal cell. Due to the lack of appropriate therapeutics or remedial treatment methods, new treatment strategies against HCC need to be developed. Cyclin dependent kinases (CDKs) are required to control the cell cycle and apoptosis, but their overexpressionis critical in the progression of cancer and is often expressed in HCC. Thus, CDKs are considered a promising class of target-defined therapy for HCC. Milciclib is a potential candidate for HCC which exhibits inhibitory activity against CDK2 leading to cell cycle arrest and apoptosis of tumor cells. Herein, we have halogenated the parent drug milciclib to improve its efficacy against CDK2. The primary structure of milciclib (D) was modified with F, Cl and,CF3 groups. The frontier molecular orbital features, binding affinity, non-bonded interaction and the pharmacokinetic parameters were analyzed for milciclib and its derivatives. We also performed molecular docking and extended molecular dynamics simulation studies to study the binding interactions and binding affinity more closely. Our computational investigation showed the derivatives D-F and D-CF3 have significant chemical reactivity, the best binding affinity, nonbonding interactions, and improved pharmacokinetic properties compared to the parent drug milciclib. Molecular dynamics analysis and MM-PBSA calculations indicated that D-Cl had a slightly more stable conformation and higher binding affinity compared to D-CF3. •Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer with no acceptable remedial therapy.•Milciclib exhibits inhibitory activity against CDK2 and therefore, is a potential candidate for HCC treatment.•The parent drug milciclib (D) can be halogenated with the F, Cl, and CF3 groups using bioinformatics techniques.•Modified derivatives exhibit way stronger interaction against CDK2 in molecular docking analyses.•In molecular dynamics simulation study, D-Cl and D-CF3 exhibit better stability and higher binding affinity than others.•Highlights Also, the derivatives have better pharmacokinetic properties compared to the parent drug which reveal their potentiality.