In silico quantitative structure-activity relationship studies on P-gp modulators of tetrahydroisoquinoline-ethyl-phenylamine series.
BACKGROUND
Multidrug resistance (MDR) is a major obstacle in cancer chemotherapy. The drug efflux by a transport protein is the main reason for MDR. In humans, MDR mainly occurs when the ATP-binding cassette (ABC) family of proteins is overexpressed simultaneously. P-glycoprotein (P-gp) is most commonly associated with human MDR; it utilizes energy from adenosine triphosphate (ATP) to transport a number of substrates out of cells against concentration gradients. By the active transport of substrates against concentration gradients, intracellular concentrations of substrates are decreased. This leads to the cause of failure in cancer chemotherapy.


RESULTS
Herein, we report Topomer CoMFA (Comparative Molecular Field Analysis) and HQSAR (Hologram Quantitative Structure Activity Relationship) models for third generation MDR modulators. The Topomer CoMFA model showed good correlation between the actual and predicted values for training set molecules. The developed model showed cross validated correlation coefficient (q2) = 0.536 and non-cross validated correlation coefficient (r2) = 0.975 with eight components. The best HQSAR model (q2 = 0.777, r2 = 0.956) with 5-8 atom counts was used to predict the activity of test set compounds. Both models were validated using test set compounds, and gave a good predictive values of 0.604 and 0.730.


CONCLUSIONS
The contour map near R1 indicates that substitution of a bulkier and polar group to the ortho position of the benzene ring enhances the inhibitory effect. This explains why compounds with a nitro group have good inhibitory potency. Molecular fragment analyses shed light on some essential structural and topological features of third generation MDR modulators. Fragments analysis showed that the presence of tertiary nitrogen, a central phenyl ring and an aromatic dimethoxy group contributed to the inhibitory effect. Based on contour map information and fragment information, five new molecules with variable R1 substituents were designed. The activity of these designed molecules was predicted by the Topomer CoMFA and HQSAR models. The novel compounds showed higher potency than existing compounds.
Departments of Bio-New Drug Development, College of Medicine, Chosun University, 375 Seosuk-dong, Dong-gu, Gwangju 501-759, Korea.
Changdev G
CG
Gadhe
Thirumurthy
T
Madhavan
Gugan
G
Kothandan
Seung Joo
SJ
Cho
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry*; D055808:Drug Discovery; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D006801:Humans; D008958:Models, Molecular; D021281:Quantitative Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000737:chemistry* / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D044005:Tetrahydroisoquinolines
J Med Chem. 2003 Nov 6;46(23):4805-17
14584929
J Chem Inf Comput Sci. 2004 Jul-Aug;44(4):1221-7
15272829
Nat Rev Drug Discov. 2006 Mar;5(3):219-34
16518375
Expert Opin Drug Metab Toxicol. 2008 Jan;4(1):1-15
18370855
Bioorg Med Chem. 2008 Mar 1;16(5):2448-62
18083034
Nat Rev Cancer. 2002 Jan;2(1):48-58
11902585
Biochem Pharmacol. 1982 Oct 1;31(19):3138-40
7150340
Cancer Res. 2003 Mar 15;63(6):1339-44
12649196
Pharmacol Res. 2003 Oct;48(4):347-59
12902205
Bioorg Med Chem. 2009 Mar 15;17(6):2524-35
19250834
J Med Chem. 2003 Jan 30;46(3):374-88
12540237
Annu Rev Pharmacol Toxicol. 1999;39:361-98
10331089
Biochemistry. 1998 Mar 17;37(11):3594-601
9530286
Bioorg Med Chem Lett. 1999 Feb 22;9(4):595-600
10098671
Bioorg Med Chem. 2006 Mar 1;14(5):1588-98
16307883
J Am Chem Soc. 1988 Aug 1;110(18):5959-67
22148765
Physiol Rev. 2006 Oct;86(4):1179-236
17015488
Cancer Control. 2003 Mar-Apr;10(2):159-65
12712010
J Med Chem. 1996 Aug 2;39(16):3060-9
8759627
Oncogene. 2003 Oct 20;22(47):7340-58
14576842