Abul Bashar Ripon Khalipha 1,2*, Rajat Bagchi 1, Md. Solayman Hossain1, Milon Mondal1, Sajal Biswas1, Pranta Ray1, Shanita Zaman Smrity1, Umma Hafsa Asha1.
1Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science & Technology University, Gopalganj, Bangladesh
2Evergreen Scientific Research Centre, Gopalganj-8100, Bangladesh
Abstract: This study aims at investigating the potential pharmacological activity of rohitukine (a bioactive chromone alkaloid) and designing newer chemical compounds against cyclin-dependent kinases (CDKs) for the treatment of cancer. Rohitukine exhibits significant anticancer, anti-inflammatory, gastroprotective, insecticidal and lipid lowering activity. Two important rohitukine analogues, flavopiridol and P276-00 potentially inhibits cyclin-dependent kinases (CDK1, CDK2, CDK4, CDK6 and CDK9) are in clinical trial II. Molecular docking studies showed that CDK9 is the best protein to which flavopiridol interacts (10.3 kcal/mol) efficiently. Two flavopiridol derivatives [N methylpyrrolidine ring substituted compound (A) and N ethylpyrrolidine ring substituted compound (B)] significantly inhibit CDK9 protein with binding affinity -10.8 kcal/mol and -10.4 kcal/mol respectively. N-fluro-pyrrolidine ring substituted Compound (D) also possesses consistent binding affinity to all CDKs proteins. The quantum mechanical calculation obtained using DFT at B3LYP/6-31G (d,p) level of theory demonstrated the charge distribution, dipole moment and thermodynamic properties of flavopiridol and the modified drugs. In silico pharmacokinetic studies also predicted that hydrophobicity, oral bioavailability, plasma protein binding was greatly enhanced in the modified compound (A), (B) and (D). These compounds also pass the blood brain barrier where the parent drug fails to penetrate the blood brain barrier. So CDK9 protein could be the potential target for compound (A) and (B) and CDK1, CDK4, CDK6 proteins for compound (D). Chemical synthesis and in vivo test on different cancer cells are required for evaluating the potentiality of this flavopiridol analogues.