title: Analysing the Effect of Mutation on Protein Function and Discovering Potential Inhibitors of CDK4: Molecular Modelling and Dynamics Studies.
abstract: The cyclin-dependent kinase 4 (CDK4)-cyclin D1 complex plays a crucial role in the transition from the G1 phase to S phase of the cell cycle. Among the CDKs, CDK4 is one of the genes most frequently affected by somatic genetic variations that are associated with various forms of cancer. Thus, because the abnormal function of the CDK4-cyclin D1 protein complex might play a vital role in causing cancer, CDK4 can be considered a genetically validated therapeutic target. In this study, we used a systematic, integrated computational approach to identify deleterious nsSNPs and predict their effects on protein-protein (CDK4-cyclin D1) and protein-ligand (CDK4-flavopiridol) interactions. This analysis resulted in the identification of possible inhibitors of mutant CDK4 proteins that bind the conformations induced by deleterious nsSNPs. Using computational prediction methods, we identified five nsSNPs as highly deleterious: R24C, Y180H, A205T, R210P, and R246C. From molecular docking and molecular dynamic studies, we observed that these deleterious nsSNPs affected CDK4-cyclin D1 and CDK4-flavopiridol interactions. Furthermore, in a virtual screening approach, the drug 5_7_DIHYDROXY_ 2_ (3_4_5_TRI HYDROXYPHENYL) _4H_CHROMEN_ 4_ONE displayed good binding affinity for proteins with the mutations R24C or R246C, the drug diosmin displayed good binding affinity for the protein with the mutation Y180H, and the drug rutin displayed good binding affinity for proteins with the mutations A205T and R210P. Overall, this computational investigation of the CDK4 gene highlights the link between genetic variation and biological phenomena in human cancer and aids in the discovery of molecularly targeted therapies for personalized treatment.
authors.affiliation: Department of Computer Sciences, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Nagasundaram
authors.initials: N
authors.lastname: N
authors.affiliation: Department of Computer Sciences, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Hailong
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Computer Sciences, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Jiming
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Computer Sciences, Hong Kong Baptist University, Kowloon Tong, Hong Kong.
authors.forename: Karthick
authors.initials: K
authors.lastname: V
authors.affiliation: Department of Computer Sciences, Hong Kong Baptist University, Kowloon Tong, Hong Kong; Medical Biotechnology Division, School of Biosciences and Technology, VIT University, Vellore, Tamil Nadu, India.
authors.forename: George Priya Doss
authors.initials: GP
authors.lastname: C
authors.affiliation: Department of Computer Sciences, Hong Kong Baptist University, Kowloon Tong, Hong Kong; Department of Bioinformatics, School of Computer and Information Sciences, Galgotias University, Greater Noida, Uttra Pradesh, India.
authors.forename: Chiranjib
authors.initials: C
authors.lastname: Chakraborty
authors.affiliation: Key Laboratory of Systems Biology, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Luonan
authors.initials: L
authors.lastname: Chen
mesh_terms: D019938:Cyclin D1 / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics*; D004353:Drug Evaluation, Preclinical; D005419:Flavonoids / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D050505:Mutant Proteins / Q000737:chemistry; D009154:Mutation / Q000235:genetics*; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D017433:Protein Structure, Secondary; D012984:Software; D013816:Thermodynamics
chemical_list: D005419:Flavonoids; D050505:Mutant Proteins; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D019938:Cyclin D1; C077990:alvocidib; D051358:Cyclin-Dependent Kinase 4