The binding modes and binding affinities of artemisinin derivatives with Plasmodium falciparum Ca2+-ATPase (PfATP6).
Noncompetitive inhibitors of sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) orthologue (PfATP6) of P. falciparum have important therapeutic value in the treatment of malaria. Artemisinin and its analogues are one such class of inhibitors which bind to a hydrophobic pocket located in the transmembrane region of PfATP6 near the biomembrane surface and interfere with calcium transport. The 3D structure of PfATP6 was modeled by homology modeling. A library consisting of 150 artemisinin analogues has been designed. Their molecular interactions and binding affinities with modeled PfATP6 protein have been studied using the docking, molecular mechanics based on generalized Born/surface area (MM-GBSA) solvation model and multi-ligand bimolecular association with energetics (eMBrAcE). Structure activity relationship models were developed between the antimalarial activity (log RA) and molecular descriptors like docking score and binding free energy. For both the cases the r(2) was in the range of 0.538-0.688 indicating good data fit and r(2)(cv) was in the range of 0.525-0.679 indicating that the predictive capabilities of the models were acceptable. Besides, a scheme similar to linear response was used to develop free energy of binding (FEB) relationship based on electrostatic (∆G(ele)), van der Waal (∆G(vdW)) and surface accessible surface area (SASA), which can express the activity of these artemisinin derivatives. It has been seen that ∆G(vdW) has most significant correlation to the activity (log RA) and electrostatic energy (∆G(ele)) has less significant correlation. It indicates that the binding of these artemisinin derivatives to PfATP6 is almost hydrophobic. Low levels of root mean square error for the majority of inhibitors establish the docking, Prime/MM-GBSA and eMBrAcE based prediction model is an efficient tool for generating more potent and specific inhibitors of PfATP6 by testing rationally designed lead compound based on artemisinin derivatization.
Naik
Pradeep Kumar
PK
Department of Biotechnology and Bioinformatics, Jaypee University of Information Technology, Waknaghat, Solan, Himachal Pradesh, India. pknaik73@rediffmail.com
Srivastava
Mani
M
Bajaj
Prasad
P
Jain
Sankalp
S
Dubey
Abhishek
A
Ranjan
Piyush
P
Kumar
Rishay
R
Singh
Harvinder
H
D000595:Amino Acid Sequence; D000962:Antimalarials / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D037621:Artemisinins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D000252:Calcium-Transporting ATPases / Q000737:chemistry* / Q000378:metabolism*; D003198:Computer Simulation; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000201:enzymology*; D011485:Protein Binding; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D055672:Static Electricity; D013329:Structure-Activity Relationship
C513500:ATP6 protein, Plasmodium falciparum; D000962:Antimalarials; D037621:Artemisinins; D008024:Ligands; C031327:artemisinin; D000252:Calcium-Transporting ATPases
J Med Chem. 1995 Dec 22;38(26):5038-44
8544180
J Med Chem. 1989 Jun;32(6):1249-52
2657065
Microbes Infect. 2004 Nov;6(14):1339-46
15555542
J Struct Biol. 2003 Jan;141(1):63-76
12576021
J Comput Aided Mol Des. 1997 Sep;11(5):425-45
9385547
Methods Enzymol. 1997;277:396-404
9379925
Science. 1985 May 31;228(4703):1049-55
3887571
Science. 2004 Jun 11;304(5677):1672-5
15192230
Nature. 2002 Aug 8;418(6898):605-11
12167852
Antimicrob Agents Chemother. 1998 Mar;42(3):682-6
9517951
J Org Chem. 2000 Mar 10;65(5):1578-82
10814129
Nat Rev Mol Cell Biol. 2004 Apr;5(4):282-95
15071553
Nature. 2004 Jul 29;430(6999):529-35
15229613
Antimicrob Agents Chemother. 2003 Mar;47(3):1175
12604568
J Comput Chem. 2002 Jan 30;23(2):214-21
11924735
Ann Trop Med Parasitol. 1985 Aug;79(4):367-74
3907556
J Mol Biol. 1963 Jul;7:95-9
13990617
J Med Chem. 2004 Mar 25;47(7):1739-49
15027865
J Chem Inf Model. 2005 Mar-Apr;45(2):366-70
15807501
Curr Med Chem. 2001 Dec;8(15):1803-26
11772352
Exp Parasitol. 1993 Feb;76(1):85-95
8467901
Nature. 2000 Jun 8;405(6787):647-55
10864315
Nature. 2002 Oct 3;419(6906):498-511
12368864
Nat Struct Mol Biol. 2005 Jul;12(7):628-9
15937493
J Comput Aided Mol Des. 1998 Mar;12(2):165-81
9690175
J Med Chem. 1992 Jun 26;35(13):2459-67
1619620
J Med Chem. 1993 Aug 20;36(17):2552-7
8355254
Nature. 2003 Aug 21;424(6951):957-61
12931192
J Med Chem. 1996 Jul 19;39(15):2900-6
8709124
J Biol Chem. 1999 Jul 2;274(27):19383-8
10383451