Prospective Virtual Screening for Novel P53-MDM2 Inhibitors Using Ultrafast Shape Recognition

Supporting Information

Prospective Virtual Screening for Novel p53-MDM2 Inhibitors Using Ultrafast Shape Recognition

Sachin P. Patil1,*, Pedro J. Ballester2, Cassidy R. Kerezsi3

1NanoBio Laboratory, Department of Chemical Engineering, Widener University, Chester, PA 19013 USA

2European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK

3Department of Biomedical Engineering, Widener University, Chester, PA 19013, USA

*To whom all correspondence should be addressed. Phone: (610) 499-4492.

Fax: (610) 499-4059. E-mail:

I. Induced-fit docking poses for USR hits

The binding modes of fourtop-ranking USR hits, obtained through induced-fit docking followed by minimization, are shown (Fig. S1).

Fig. S1The binding modes of 4 USR hits. (Left panel) surface representation of p53-binding pocket on MDM2 containing bound ligands, (right panel) 2D ligand-protein interaction diagrams

Fig. S1 continued

II. Molecular docking using Autodock Vina

Crystal structure of MDM2 protein (PDB: 3LBL) downloaded from the protein data bank (PDB) [1] was used for the docking study. The protein was processed using the AutoDock Tools utility, whereby bound ligands and water molecules were removed, polar hydrogen was added, non-polar hydrogen was merged, and Gasteiger charges were assigned for all the atoms in the protein. The MDM2 protein and ligand atoms were converted into PDBQT format. Structure-based docking of the USR-selected molecules to the p53-binding site of MDM2 was then carried out using the docking program AutoDock Vina [2]. The search space coordinates were: Center X:-28.9098, Y:17.4573, Z:-50.1283; Dimensions (Å) X:38.5244, Y:32.8518, Z:32.6208. Default docking parameters were used throughout the simulations. The molecules were then ranked according to their best docking score values, which are reported in Table S1 below.

Table S1Autodock Vina docking scores for top USR hits

Molecules Vina Docking Score (Kcal/mol)

Query: MI-63 -10.0

ZINC01530886 -8.9

ZINC12504151 -8.0

ZINC12501050 -8.2

ZINC03872863 -8.1

ZINC03817099 -7.6

ZINC12502561 -7.5

III. The NCI60 Screening Assay

Telmisartan was subjected to in vitro cancer cell line screening through the National Cancer Institute Developmental Therapeutics Program (NCI-DTP) 60 human tumor cell line panel (NCI60). The NCI60 screening methodology is explained on the NCI-DTP website ( The p53 status of these human tumor cell lines have been reported previously by O'Connor et al. [3]. The screening data are presented in Table S2 and Fig. S2.

Table S2The NCI60 screening data for telmisartan

Wt-p53 Cell Line GI50 (µM) Mut-p53 Cell Line GI50 (µM)

MOLT-432.4 CCRF-CEM 22.9

RPMI-822617.4 HL-60(TB) 28.8

SR28.8 K-562 23.4

A549/ATCC22.9HOP-6243.7

NCI-H46032.4HOP-9225.7

HCT-11643.7NCI-H226 32.4

HCT-1520.4NCI-H2351.3

SF-53946.8NCI-H322M100

LOX IMVI23.4NCI-H522 21.9

MALME-3M45.7COLO 205 42.7

SK-MEL-236.3HCC-2998 52.5

SK-MEL-525.7HT29 35.5

UACC-25767.6SW-620 49.0

UACC-6222.4SF-268 43.7

IGROV143.7SF-295 34.7

OVCAR-450.1SNB-1939.8

A49820.4SNB-7556.2

ACHN25.7U25120.4

CAKI-122.4M14 34.7

UO-3119.1SK-MEL-2825.7

MCF731.6OVCAR-3 14.8

OVCAR-5100

OVCAR-8 35.5

NCI/ADR-RES41.7

SK-OV-3100

786-0 41.7

RXF 393 22.4

SN12C33.1

TK-1056.2

PC-329.5

DU-145 43.7

MDAMB-231/ATCC 30.2

HS 578T38.0

BT-549 52.5

T-47D 49.0

MDA-MB-468 37.2

Fig. S2 The GI50 values for telmisartan in wt-p53 versus mut-p53 cell lines in the NCI60 screen

References

1. Berman HM, Westbrook J, Feng, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE (2000) The Protein Data Bank. Nucleic Acids Research 1:235-242

2. Trott O, Olson AJ (2010) AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. Journal of Computational Chemistry 2:455-461

3. O'Connor PM, Jackman J, Bae I, Myers TG, Fan S, Mutoh M, Scudiero DA, Monks A, Sausville EA, Weinstein JN, Friend S, Fornace AJ Jr, Kohn KW (1997) Characterization of the p53 tumor suppressor pathway in cell lines of the National Cancer Institute anticancer drug screen and correlations with the growth-inhibitory potency of 123 anticancer agents. Cancer Research 57(19):4285-4300

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