Two widely used anticancer drugs, doxorubicin (DOX) and paclitaxel (PTX), possess distinct physical properties and chemotherapy specificity. In order to investigate their interaction mechanism with single-walled carbon nanotubes (SWCNTs), co-loading and releasing from the SWCNTs, all-atom molecular dynamics (MD) simulations were firstly carried out for different SWCNT systems, followed by binding free energy calculation with MM-PBSA. The results indicate that the co-loading of DOX and PTX onto the pristine SWCNT is exothermic and spontaneous. The DOX molecules predominantly interact with the SWCNT via π-π stacking through the conjugated aromatic rings, while the separated aromatic rings of PTX also primarily interact with the SWCNT through π-π stacking yet supplemented by an X-π (X = C-H, N-H and C[double bond, length as m-dash]O) interaction. Moreover, the strongest binding of DOX and PTX with the pristine SWCNT shows similar strength (ΔG: -32.0 vs. -33.8 kcal mol-1). For the chitosan functionalized SWCNT (f-SWCNT), the DOX and PTX molecules still prefer binding to the sidewall of the CNT rather than binding with the polymer, and the non-covalent functionalization of the SWCNT with chitosan decreases the binding of DOX and PTX with the sidewall of the f-SWCNT as compared with the DOX/PTX-SWCNT system (ΔG: -24.0 and -21.9 kcal mol-1). The protonation of chitosan and drug molecules further weakens the interaction between DOX/PTX and the f-SWCNT, and shows a consequent displacement of the drug molecules, triggering the release of the drugs. The variation of binding strength of the three systems (DOX/PTX-SWCNT, DOX/PTX-f-SWCNT, and DOXH+/PTXH+-f-SWCNT) was also discussed in terms of the histogram or frequency of the distance from the drugs to the SWCNT. In addition, the encapsulation of two DOX molecules by the f-SWCNT is considerably stronger than the binding of the other six drug molecules to the sidewall, indicating that the encapsulation of anticancer drugs may also play a very important role and should be considered in the drug delivery.

Cyclin-dependent kinases (CDKs) are core components of the cell cycle machinery that govern the transition between phases during cell cycle progression. Abnormalities in CDKs activity and regulation are common features of cancer, making CDK family members attractive targets for the development of anticancer drugs. Their inhibitors have entered in clinical trials to treat cancer. Very recently, Heathcote et al. (J. Med. Chem. 2010, 53:8508-8522) have found a ligand BS194 that has a high affinity with CDK2 (IC(50) = 3 nM) but shows low affinity with CDK1 (IC(50) = 30 nM). To understand the selectivity, we used homology modeling, molecular docking, molecular dynamics, and free-energy calculation to analyze the interactions. A rational three-dimensional model of the CDK1/BS194 complex is built. We found that Leu83 is a key residue that recognizes BS194 more effectively with CDK2 with good binding free energies rather than CDK1. Energetic analysis reveals that van der Waals interaction and non-polar contributions to solvent are favorable in the formation of complexes and amine group of the ligand, which plays a crucial role for binding selectivity between CDK2 and CDK1.

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