title: Hybrid quantum mechanical/molecular mechanical molecular dynamics simulations of HIV-1 integrase/inhibitor complexes.
abstract: Human immunodeficiency virus (HIV)-1 integrase (IN) is an attractive target for development of acquired immunodeficiency syndrome chemotherapy. In this study, conventional and coupled quantum mechanical and molecular mechanical (QM/MM) molecular dynamics (MD) simulations of HIV-1 IN complexed with 5CITEP (IN-5CITEP) were carried out. In addition to differences in the bound position of 5CITEP, significant differences at the two levels of theory were observed in the metal coordination geometry and the areas involving residues 116-119 and 140-166. In the conventional MD simulation, the coordination of Mg(2+) was found to be a near-perfect octahedral geometry whereas a distorted octahedral complex was observed in QM/MM. All of the above reasons lead to a different pattern of protein-ligand salt link formation that was not observed in the classical MD simulation. Furthermore to provide a theoretical understanding of inhibition mechanisms of 5CITEP and its derivative (DKA), hybrid QM/MM MD simulations of the two complexes (IN-5CITEP and IN-DKA) have been performed. The results reveal that areas involving residues 60-68, 116-119, and 140-149 were substantially different among the two systems. The two systems show similar pattern of metal coordination geometry, i.e., a distorted octahedron. In IN-DKA, both OD1 and OD2 of Asp-64 coordinate the Mg(2+) in a monodentate fashion whereas only OD1 is chelated to the metal as observed in IN-5CITEP. The high potency of DKA as compared to 5CITEP is supported by a strong salt link formed between its carboxylate moiety and the ammonium group of Lys-159. Detailed comparisons between HIV-1 IN complexed with DKA and with 5CITEP provide information about ligand structure effects on protein-ligand interactions in particular with the Lys-159. This is useful for the design of new selective HIV-1 IN inhibitors.
authors: Department of Chemistry, Faculty of Science, Chulalongkorn University, Bangkok, Thailand.
authors: Nadtanet
authors: N
authors: Nunthaboot
authors: Somsak
authors: S
authors: Pianwanit
authors: Vudhichai
authors: V
authors: Parasuk
authors: Jerry O
authors: JO
authors: Ebalunode
authors: James M
authors: JM
authors: Briggs
authors: Sirirat
authors: S
authors: Kokpol
mesh_terms: D002264:Carboxylic Acids / Q000737:chemistry; D003198:Computer Simulation; D019427:HIV Integrase / Q000737:chemistry*; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D008239:Lysine / Q000737:chemistry; D008274:Magnesium / Q000737:chemistry; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry; D011789:Quantum Theory; D012492:Salts / Q000737:chemistry; D014867:Water / Q000737:chemistry
chemical_list: D002264:Carboxylic Acids; D019428:HIV Integrase Inhibitors; D008024:Ligands; D011506:Proteins; D012492:Salts; D014867:Water; D019427:HIV Integrase; D008274:Magnesium; D008239:Lysine; C514801:p31 integrase protein, Human immunodeficiency virus 1
references: J Med Chem. 2005 Mar 24;48(6):1930-40
references: 15771437
references: J Med Chem. 2005 Jan 13;48(1):111-20
references: 15634005
references: J Mol Graph Model. 2007 Jul;26(1):1-13
references: 17046299
references: Biophys J. 2005 May;88(5):3072-82
references: 15764656
references: Bioorg Med Chem Lett. 2004 Mar 22;14(6):1447-54
references: 15006380
references: J Med Chem. 2004 Apr 8;47(8):1879-81
references: 15055986
references: J Mol Biol. 1989 Jul 5;208(1):159-81
references: 2769750
references: Nat Rev Drug Discov. 2005 Mar;4(3):236-48
references: 15729361
references: J Med Chem. 2005 Dec 15;48(25):8009-15
references: 16335925
references: J Med Chem. 2004 Dec 30;47(27):6673-80
references: 15615516
references: J Med Chem. 2005 Jul 14;48(14):4526-34
references: 15999991
references: J Med Chem. 2004 May 6;47(10):2561-73
references: 15115398
references: Bioorg Med Chem. 2004 Dec 15;12(24):6371-81
references: 15556755
references: Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9150-4
references: 9689049
references: Bioorg Med Chem Lett. 2006 Apr 1;16(7):1920-3
references: 16439124
references: J Med Chem. 2001 Sep 13;44(19):3043-7
references: 11543671
references: Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):10080-5
references: 16785440
references: Mol Pharmacol. 2003 Sep;64(3):600-9
references: 12920196
references: Bioorg Med Chem. 2006 Jul 1;14(13):4552-67
references: 16524737
references: J Am Chem Soc. 2005 Mar 30;127(12):4454-65
references: 15783228
references: Curr Top Med Chem. 2004;4(9):965-77
references: 15134551
references: J Am Chem Soc. 2001 Dec 19;123(50):12708-9
references: 11741448
references: J Med Chem. 2006 Jul 13;49(14):4248-60
references: 16821784
references: Biophys J. 2003 Mar;84(3):1450-63
references: 12609852
references: Biophys J. 2005 May;88(5):3133-46
references: 15731379
references: J Med Chem. 2006 Mar 23;49(6):1939-45
references: 16539381
references: J Mol Graph. 1996 Feb;14(1):33-8, 27-8
references: 8744570
references: J Phys Chem B. 1998 Apr 30;102(18):3586-616
references: 24889800
references: Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13040-3
references: 10557269
references: J Phys Chem B. 2005 Aug 18;109(32):15645-50
references: 16852982
references: Bioorg Med Chem. 2006 Dec 15;14(24):8420-9
references: 17005407
references: J Med Chem. 2007 Mar 22;50(6):1133-45
references: 17302399
references: Proc Natl Acad Sci U S A. 1985 Dec;82(24):8458-62
references: 3866234
references: J Med Chem. 2004 Oct 21;47(22):5583-6
references: 15481994
references: J Med Chem. 2004 Oct 7;47(21):5298-310
references: 15456274
references: Proteins. 2005 Jun 1;59(4):723-41
references: 15815973
references: Bioorg Med Chem. 2007 Feb 1;15(3):1212-28
references: 17158051
references: Proteins. 2003 Feb 15;50(3):451-63
references: 12557187
references: J Biol Chem. 1997 Jul 18;272(29):18161-8
references: 9218451
references: Proc Natl Acad Sci U S A. 2002 May 14;99(10):6661-6
references: 11997448
references: Biophys J. 1999 Jun;76(6):2999-3011
references: 10354426
references: J Med Chem. 2005 Nov 3;48(22):7084-8
references: 16250669