Conception de médicaments : accès ouvert
Libre accès
ISSN: 2169-0138
ISSN: 2169-0138
Bondin M and Shoemake C
This project utilised Verapamil as a lead molecule for iterative design of novel anti-cancer drugs with the potential to inhibit P-Glycoprotein (P-gp), a target which is overexpressed in malignant cells. The protein data bank crystallographic deposition 4M2S, describing the bound co-ordinates of P-gp bound to the small antagonist molecule QZ59-RRR, was used as a template for this study. Two drug design approaches were employed- de novo design and virtual screening (VS). For the former, the SYBYL®-X v1.1 software was used to generate the apo-receptor (empty receptor) and QZ59-RRR extract. Both chiral forms of Verapamil, R and S, were sketched and docked into the P-gp receptor using SYBYL®-X v1.1. 20 optimal conformations were identified and those possessing the best combination of high ligand binding affinity (pKd) and low ligand binding energy (Kcal mol-1) were selected for further analysis. For each of the latter, seed structures were generated based on structure activity relationships (SAR) identified from literature and Poseview®. LigBuilder® v1.2 was used to generate 560 de novo molecules. In the VS approach, the online database ViCi® hosted at the University of Hamburg found 1000 molecules with similar physicochemical properties to the optimal conformations of Verapamil, which served as query molecules in this approach. These were then docked into the protomol, generated in SYBYL®-X v1.1. 107 of the de novo designed molecules and 988 of the virtual screening molecules satisfied Lipinski's Rules. Of these, 88 of the de novo designed molecules had a pKd higher than the templates and 48 of the molecules identified through VS had a pKd that exceeded an arbitrarily set acceptable value of 6. These molecules were subsequently analysed and used to propose a pharmacophore that could be used as a guide in further design of high affinity modulators of P-gp.