ABSTRACT
The discovery of ATP competitive CDK4 inhibitors is an on-going challenging task in cancer therapy. Here, an attempt has been made to develop new leads targeting ATP binding site of CDK4 by applying 3D-QSAR pharmacophore mapping and molecular docking methods The outcome of 6 leads offers a significant contribution for selective CDK4 inhibition, since they show potential binding interactions with Val96, Arg101, and Glu144 residues of CDK4, that are unique and from other kinases. It is worth noting that there is a striking similarity in binding interactions of the leads and known CDK4 inhibitors, namely Abemaciclib, Palbociclib and Ribociclib. Further key features, including high dock score value, good predicted activity, scaffold diversity, and the acceptable ADME profile of leads, provide a great opportunity for the development of highly potent and selective ATP competitive inhibitors of CDK4.
Subject(s)
Adenosine Triphosphate/chemistry , Cyclin-Dependent Kinase 4/chemistry , Drug Discovery , Molecular Docking Simulation , Quantitative Structure-Activity Relationship , Aminopyridines/chemistry , Aminopyridines/pharmacology , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Binding Sites/drug effects , Cyclin-Dependent Kinase 4/antagonists & inhibitors , Humans , Piperazines/chemistry , Piperazines/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Purines/chemistry , Purines/pharmacology , Pyridines/chemistry , Pyridines/pharmacologyABSTRACT
Cancer is a class of diseases characterized by uncontrolled cell growth. Every year more than 2 million people are affected by the disease. Rho family proteins are actively involved in cytoskeleton regulation. Over-expression of Rho family proteins show oncogenic activity and promote cancer progression. In the present work RhoG protein is considered as novel target of cancer. It is a member of Rho family and Rac subfamily protein, which plays pivotal role in regulation of microtubule formation, cell migration and contributes in cancer progression. In order to understand the binding interaction between RhoG protein and the DH domain of Ephexin-4 protein, the 3D structure of RhoG was evaluated and Molecular Dynamic Simulations was performed to stabilize the structure. The 3D structure of RhoG protein was validated and active site identified using standard computational protocols. Protein-protein docking of RhoG with Ephexin-4 was done to understand binding interactions and the active site structure. Virtual screening was carried out with ligand databases against the active site of RhoG protein. The efficiency of virtual screening is analysed with enrichment factor and area under curve values. The binding free energy of docked complexes was calculated using prime MM-GBSA module. The SASA, FOSA, FISA, PISA and PSA values of ligands were carried out. New ligands with high docking score, glide energy and acceptable ADME properties were prioritized as potential inhibitors of RhoG protein.
Subject(s)
Antineoplastic Agents/chemistry , Drug Design , Molecular Docking Simulation , Molecular Dynamics Simulation , rho GTP-Binding Proteins/chemistry , Antineoplastic Agents/pharmacology , Binding Sites , Drug Discovery , Ligands , Molecular Conformation , Protein Binding , ROC Curve , Solvents , Structure-Activity Relationship , rho GTP-Binding Proteins/antagonists & inhibitorsABSTRACT
BACKGROUND: The Rab family proteins are involved in membrane trafficking, cell growth and differentiation. Rab38 is implicated in the biogenesis of melanosomes that help in the synthesis, storage and transport of melanin pigments. The Rab38 protein is overexpressed at the RNA level in melanoma cancer. AIM AND OBJECTIVE: The protein Rab38 is targeted for identification of novel antagonists as cancer drug candidates. MATERIALS AND METHODS: The 3D structure of Rab38 was generated using homology modelling method. The 3D model was validated. The active site was identified by using standard computational prediction tools like CASTp, efindsite and SiteMap. The study of protein-protein docking was performed between Rab38 and its natural substrate BLOC-3 using patchDock server tool. Virtual screening protocols were carried out using glide module. Various informatics tools like 1) Schrodinger Suite 2) Modeller 3) Accelrys Discovery Studio 4) PyMOL 5) SPDBV etc. are applied for the identification of novel inhibitors of Rab38. RESULTS: The residues from SER35 to LEU63 of Rab38 protein are important for binding to ligands. The nineteen docked structures were obtained as an output of virtual screening. The compounds obtained show good glide score, and a common binding pattern at the active site. CONCLUSION: The benzosulfonamide and heterocyclic nitrogen moieties may be considered as pharmacophores for designing new anticancer leads with better docking score and admissible ADME properties. Our study helps in the identification of potential inhibitors against Rab38 and melanoma cancer.
