Poly(ADP-ribose) polymerase (PARP) is regarded as a target protein for paclitaxel (PTX) to bind. An important issue is to identify the key residues as active sites for PTX interacting with PARP, which will help to understand the potential drug activity of PTX against cancer cells. Using docking method and MD simulation, we have constructed a refined structure of PTX docked on the catalytic function domain of PARP (PDB code: 1A26). The residues Glu327(988), Tyr246(907), Lys242(903), His165(826), Asp105(766), Gln102(763) and Gln98(759) in PARP are identified as potential sites involved in interaction with PTX according to binding energy (E_b) between PTX and single residue calculated with B3LYP/6-31G(d,p). These residues form an active binding pocket located on the surface of the catalytic fragment, possibly interacting with the required groups of PTX leading to its activity against cancer cells. It is noted that most of the active sites make conatct with the “southern hemisphere” of PTX except for one residue, Tyr246(907), which interacts with the “nourthern hemisphere” of PTX. The conformation of PTX in complex with the catalytic fragment is observed as being T-shaped, similar to that complexed with β-tubulin. The total Eb of -269.9 kJ/mol represents the potent interaction between PTX and the catalytic fragment, implying that PTX can readily bind to the active pocket. The tight association of PTX with the catalytic fragment would inhibit PARP activation, suggesting a potential application of PTX as an effective antineoplastic agent.

Key words: Binding pocket; Active site; Paclitaxel; Poly(ADP-Ribose) Polymerase; MD simulation; DFT.

This article can be cited as:
Y. Wang, F. Bian, S. Deng, Q. Shi, M. Ge, S. Wang, X. Zhang, S. Xu, The Key Residues of Active Sites on the Catalytic Fragment for Paclitaxel Interacting with Poly (ADP-Ribose) Polymerase, J. Biomol Struct Dyn 28(6), 881-893 (2011).