Binding modes of diketo-acid inhibitors of HIV-1 integrase: A comparative molecular dynamics simulation study

Graphical abstract Highlights ► Comparative molecular dynamics simulations on HIV-1 IN bound with L-731,988, L-708,906 and S-1360. ► The acidic end of all the DKA inhibitors studied formed favourable ionic interactions with Lys159. ► The keto–enol parts of these compounds were consistently coordinated to Mg. ► The catalytic residue Glu152 formed a favourable ion–pair interaction with the negatively charged Arg199 on α6 in the most potent DKA inhibitors. ► The complexation with Merck inhibitors and S-1360 significantly constrained the flexible surface loop into an extended or open conformation.

[1]  Marc C Nicklaus,et al.  Metal-dependent inhibition of HIV-1 integrase by beta-diketo acids and resistance of the soluble double-mutant (F185K/C280S). , 2003, Molecular pharmacology.

[2]  J. Andrew McCammon,et al.  HIV-1 Integrase Inhibitor Interactions at the Active Site: Prediction of Binding Modes Unaffected by Crystal Packing , 2000 .

[3]  Yong Duan,et al.  Large-scale conformational dynamics of the HIV-1 integrase core domain and its catalytic loop mutants. , 2005, Biophysical journal.

[4]  J A Grobler,et al.  Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. , 2000, Science.

[5]  M. Markowitz,et al.  Raltegravir: an integrase inhibitor for HIV-1 , 2008, Expert opinion on investigational drugs.

[6]  M Karplus,et al.  Solvent effects on protein motion and protein effects on solvent motion. Dynamics of the active site region of lysozyme. , 1989, Journal of molecular biology.

[7]  B. Clotet,et al.  The HIV-1 integrase genotype strongly predicts raltegravir susceptibility but not viral fitness of primary virus isolates , 2010, AIDS.

[8]  B. Stoddard,et al.  Comparative architecture of transposase and integrase complexes , 2001, Nature Structural Biology.

[9]  J A McCammon,et al.  Ordered water and ligand mobility in the HIV-1 integrase-5CITEP complex: a molecular dynamics study. , 2001, Journal of medicinal chemistry.

[10]  M. Karplus,et al.  CHARMM: A program for macromolecular energy, minimization, and dynamics calculations , 1983 .

[11]  V. Mikol,et al.  Crystal structures of the catalytic domain of HIV-1 integrase free and complexed with its metal cofactor: high level of similarity of the active site with other viral integrases. , 1998, Journal of molecular biology.

[12]  A. Engelman,et al.  Critical contacts between HIV‐1 integrase and viral DNA identified by structure‐based analysis and photo‐crosslinking , 1997, The EMBO journal.

[13]  W. L. Jorgensen,et al.  Comparison of simple potential functions for simulating liquid water , 1983 .

[14]  I. Tuñón,et al.  A quantum mechanic/molecular mechanic study of the wild-type and N155S mutant HIV-1 integrase complexed with diketo acid. , 2008, Biophysical journal.

[15]  I Kolossváry,et al.  Fully flexible low-mode docking: application to induced fit in HIV integrase. , 2001, Journal of the American Chemical Society.

[16]  F. Bushman,et al.  Identification of discrete functional domains of HIV‐1 integrase and their organization within an active multimeric complex. , 1993, The EMBO journal.

[17]  D. Davies,et al.  Three new structures of the core domain of HIV-1 integrase: an active site that binds magnesium. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[18]  G. Cohen,et al.  Structure of the HIV-1 integrase catalytic domain complexed with an inhibitor: a platform for antiviral drug design. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[19]  F. Bailly,et al.  Structure-activity relationships of HIV-1 integrase inhibitors--enzyme-ligand interactions. , 2003, Current medicinal chemistry.

[20]  Amy S. Espeseth,et al.  Diketo acid inhibitor mechanism and HIV-1 integrase: Implications for metal binding in the active site of phosphotransferase enzymes , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[21]  R. Dayam,et al.  Small-molecule HIV-1 integrase inhibitors: the 2001-2002 update. , 2003, Current pharmaceutical design.

[22]  Federico Fogolari,et al.  Comparative molecular dynamics simulations of HIV‐1 integrase and the T66I/M154I mutant: Binding modes and drug resistance to a diketo acid inhibitor , 2005, Proteins.

[23]  Vasu Nair.  Novel Inhibitors of HIV Integrase: The Discovery of Potential Anti-HIV Therapeutic Agents , 2005 .

[24]  Sergio Martí,et al.  A quantum mechanics/molecular mechanics study of the protein-ligand interaction for inhibitors of HIV-1 integrase. , 2007, Chemistry.

[25]  A. Engelman,et al.  Retroviral intasome assembly and inhibition of DNA strand transfer , 2010, Nature.

[26]  Alba Chimirri,et al.  Molecular dynamics studies of the wild-type and double mutant HIV-1 integrase complexed with the 5CITEP inhibitor: mechanism for inhibition and drug resistance. , 2003, Biophysical journal.

[27]  R. Plasterk,et al.  Complementation between HIV integrase proteins mutated in different domains. , 1993, The EMBO journal.

[28]  Alexander D. MacKerell,et al.  All-atom empirical potential for molecular modeling and dynamics studies of proteins. , 1998, The journal of physical chemistry. B.

[29]  F. Bushman,et al.  The mobility of an HIV-1 integrase active site loop is correlated with catalytic activity. , 1999, Biochemistry.

[30]  R M Stroud,et al.  Crystal structure of the HIV-1 integrase catalytic core and C-terminal domains: a model for viral DNA binding. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[31]  Yves Pommier,et al.  Comparison of raltegravir and elvitegravir on HIV-1 integrase catalytic reactions and on a series of drug-resistant integrase mutants. , 2008, Biochemistry.

[32]  J. Briggs,et al.  Investigations on human immunodeficiency virus type 1 integrase/DNA binding interactions via molecular dynamics and electrostatics calculations. , 2000, Pharmacology & therapeutics.

[33]  A. Bax,et al.  Solution Conformation and Dynamics of the HIV-1 Integrase Core Domain* , 2010, The Journal of Biological Chemistry.

[34]  M. Jaskólski,et al.  High-resolution structure of the catalytic domain of avian sarcoma virus integrase. , 1995, Journal of molecular biology.

[35]  J Andrew McCammon,et al.  Discovery of a novel binding trench in HIV integrase. , 2004, Journal of medicinal chemistry.

[36]  M. Parker,et al.  Crystal structure of the HIV‐1 integrase core domain in complex with sucrose reveals details of an allosteric inhibitory binding site , 2010, FEBS letters.

[37]  E. De Clercq,et al.  Multiple mutations in human immunodeficiency virus-1 integrase confer resistance to the clinical trial drug S-1360 , 2004, AIDS.

[38]  Y. Pommier,et al.  Integrase inhibitors to treat HIV/Aids , 2005, Nature Reviews Drug Discovery.

[39]  S. Wahl,et al.  The mouth: a gateway or a trap for HIV? , 2010, AIDS.

[40]  J. Briggs,et al.  Hybrid quantum mechanical/molecular mechanical molecular dynamics simulations of HIV-1 integrase/inhibitor complexes. , 2007, Biophysical journal.

[41]  D. Esposito,et al.  Sequence specificity of viral end DNA binding by HIV‐1 integrase reveals critical regions for protein–DNA interaction , 1998, The EMBO journal.

[42]  Mark Embrey,et al.  A naphthyridine carboxamide provides evidence for discordant resistance between mechanistically identical inhibitors of HIV-1 integrase. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[43]  Robert Craigie,et al.  HIV-1 DNA integration: Mechanism of viral DNA cleavage and DNA strand transfer , 1991, Cell.

[44]  A. Billich.  S-1360 Shionogi-GlaxoSmithKline. , 2003, Current opinion in investigational drugs.

[45]  J. Briggs,et al.  Comparison of multiple molecular dynamics trajectories calculated for the drug-resistant HIV-1 integrase T66I/M154I catalytic domain. , 2005, Biophysical journal.

[46]  H. M. Langford,et al.  4-Aryl-2,4-dioxobutanoic acid inhibitors of HIV-1 integrase and viral replication in cells. , 2000, Journal of medicinal chemistry.

[47]  Lisa Yan,et al.  A fast and accurate computational approach to protein ionization , 2008, Protein science : a publication of the Protein Society.

[48]  I. Tuñón,et al.  Calculation of binding energy using BLYP/MM for the HIV-1 integrase complexed with the S-1360 and two analogues. , 2007, Bioorganic & medicinal chemistry.