A Multivariate Analysis of HIV-1 Protease Inhibitors and Resistance Induced by Mutation

This paper describes the use of the multivariate statistical procedure principal component analysis as a tool to explore the inhibitory activity of classes of protease inhibitors (PIs) against HIV-1 viruses (wild type and more-frequent single mutants, V82A, V82F, and I84V) and against protease enzymes. The analysis of correlations between biological activity and molecular descriptors or similarity indexes allowed a reliable classification of the 51 derivatives considered in this study. The best results were obtained in the case of the I84V mutant for which a high number of predictions was achieved. On this basis, this statistical approach is proposed as a reliable method for the prediction of the activity of PIs, for which the data against mutant strains have not been reported.

[1]  D. Lamarre,et al.  Antiviral properties of palinavir, a potent inhibitor of the human immunodeficiency virus type 1 protease , 1997, Antimicrobial agents and chemotherapy.

[2]  J. Barrish,et al.  Antiviral properties of aminodiol inhibitors against human immunodeficiency virus and protease , 1995, Antimicrobial agents and chemotherapy.

[3]  R A Mueller,et al.  Discovery of a novel class of potent HIV-1 protease inhibitors containing the (R)-(hydroxyethyl)urea isostere. , 1993, Journal of medicinal chemistry.

[4]  Ramon Carbo,et al.  How similar is a molecule to another? An electron density measure of similarity between two molecular structures , 1980 .

[5]  L. Vrang,et al.  Design and fast synthesis of C-terminal duplicated potent C(2)-symmetric P1/P1'-modified HIV-1 protease inhibitors. , 1999, Journal of medicinal chemistry.

[6]  A. Molla,et al.  In Vitro Antiviral Interaction of Lopinavir with Other Protease Inhibitors , 2002, Antimicrobial Agents and Chemotherapy.

[7]  S. Miertus,et al.  Computational studies of the resistance patterns of mutant HIV-1 aspartic proteases towards ABT-538 (ritonavir) and design of new derivatives. , 2002, Journal of molecular graphics & modelling.

[8]  S. Vasavanonda,et al.  ABT-538 is a potent inhibitor of human immunodeficiency virus protease and has high oral bioavailability in humans. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[9]  C. J. Huberty,et al.  Issues in the use and interpretation of discriminant analysis , 1984 .

[10]  M. Tutone,et al.  A Multivariate Analysis on Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors and Resistance Induced by Mutation , 2003 .

[11]  D. Ho,et al.  Antiviral and resistance studies of AG1343, an orally bioavailable inhibitor of human immunodeficiency virus protease , 1996, Antimicrobial agents and chemotherapy.

[12]  J L Meek,et al.  Nonpeptide cyclic cyanoguanidines as HIV-1 protease inhibitors: synthesis, structure-activity relationships, and X-ray crystal structure studies. , 1998, Journal of medicinal chemistry.

[13]  K D Watenpaugh,et al.  Tipranavir (PNU-140690): a potent, orally bioavailable nonpeptidic HIV protease inhibitor of the 5,6-dihydro-4-hydroxy-2-pyrone sulfonamide class. , 1998, Journal of medicinal chemistry.

[14]  Hiroshi Harada,et al.  S-1153 Inhibits Replication of Known Drug-Resistant Strains of Human Immunodeficiency Virus Type 1 , 1998, Antimicrobial Agents and Chemotherapy.

[15]  T. Bhat,et al.  Cyclopropane-derived peptidomimetics. Design, synthesis, evaluation, and structure of novel HIV-1 protease inhibitors. , 1998, Journal of medicinal chemistry.

[16]  H. Ikigai,et al.  Inhibitory effects of (-)-epigallocatechin gallate on the life cycle of human immunodeficiency virus type 1 (HIV-1). , 2002, Antiviral research.

[17]  R. Myers,et al.  In vitro selection and characterization of human immunodeficiency virus type 1 (HIV-1) isolates with reduced sensitivity to hydroxyethylamino sulfonamide inhibitors of HIV-1 aspartyl protease , 1995, Journal of virology.

[18]  J. Mestan,et al.  Synthesis and Pharmacological Evaluation of CGP 57813 and CGP 61755, HIV-1 Protease Inhibitors from the Phe-c-Phe Peptidomimetic Class , 1996 .

[19]  A. Balaban.  Highly discriminating distance-based topological index , 1982 .

[20]  B. Rosenwirth,et al.  Potent and Orally Bioavailable HIV-1 Proteinase Inhibitors Containing the 2-aminobenzylstatine Moiety , 1995 .

[21]  E. Lunney,et al.  Synthesis of 5,6-dihydro-4-hydroxy-2-pyrones as HIV-1 protease inhibitors: the profound effect of polarity on antiviral activity. , 1997, Journal of medicinal chemistry.

[22]  J. Leonard,et al.  Human serum attenuates the activity of protease inhibitors toward wild-type and mutant human immunodeficiency virus. , 1998, Virology.

[23]  P. Ettmayer,et al.  Paracyclophanes: a novel class of water-soluble inhibitors of HIV proteinase. , 1996, Journal of Medicinal Chemistry.

[24]  E. Freire,et al.  A major role for a set of non-active site mutations in the development of HIV-1 protease drug resistance. , 2003, Biochemistry.

[25]  A quantitative structure-activity relationship study on some HIV-1 protease inhibitors using molecular connectivity index. , 2001, Bioorganic & medicinal chemistry.

[26]  L. Bacheler,et al.  Resistance to HIV protease inhibitors: a comparison of enzyme inhibition and antiviral potency. , 1998, Biochemistry.

[27]  Rudolf Kiralj,et al.  A priori molecular descriptors in QSAR: a case of HIV-1 protease inhibitors. I. The chemometric approach. , 2003, Journal of molecular graphics & modelling.

[28]  M. Muesing,et al.  Potent human immunodeficiency virus type 1 protease inhibitors that utilize noncoded D-amino acids as P2/P3 ligands. , 1996, Journal of medicinal chemistry.

[29]  Lemont B. Kier,et al.  An Electrotopological-State Index for Atoms in Molecules , 1990, Pharmaceutical Research.

[30]  S. Miyamoto,et al.  Structure-activity relationship of HIV-1 protease inhibitors containing α-hydroxy-β-amino acids. Detailed study of P1 site , 1999 .

[31]  C. Kubli-Garfias,et al.  Electronic structure of testosterone: A semiempirical and ab initio assessment , 1997 .

[32]  Dale J. Kempf,et al.  ABT-378, a Highly Potent Inhibitor of the Human Immunodeficiency Virus Protease , 1998, Antimicrobial Agents and Chemotherapy.

[33]  Mati Karelson,et al.  Six-membered cyclic ureas as HIV-1 protease inhibitors: a QSAR study based on CODESSA PRO approach. Quantitative structure-activity relationships. , 2002, Bioorganic & medicinal chemistry letters.

[34]  J L Meek,et al.  Improved cyclic urea inhibitors of the HIV-1 protease: synthesis, potency, resistance profile, human pharmacokinetics and X-ray crystal structure of DMP 450. , 1996, Chemistry & biology.

[35]  Arun K. Ghosh,et al.  Novel cyclourethane-derived HIV protease inhibitors: a ring-closing olefin metathesis based strategy. , 2002, Bioorganic & medicinal chemistry letters.

[36]  P. Vierling,et al.  Synthesis and Anti-HIV Activity of Prodrugs Derived from Saquinavir and Indinavir , 2000, Antiviral chemistry & chemotherapy.

[37]  Arup K. Ghose,et al.  Atomic physicochemical parameters for three dimensional structure directed quantitative structure-activity relationships. 4. Additional parameters for hydrophobic and dispersive interactions and their application for an automated superposition of certain naturally occurring nucleoside antibiotics , 1989, J. Chem. Inf. Comput. Sci..

[38]  W. Graham Richards,et al.  Similarity of molecular shape , 1991, J. Comput. Aided Mol. Des..

[39]  J. Colacino,et al.  Potent, orally bioavailable HIV-1 protease inhibitors containing noncoded D-amino acids , 1995 .

[40]  Peter C. Jurs,et al.  Classification of HIV protease inhibitors on the basis of their antiviral potency using radial basis function neural networks , 2003, J. Comput. Aided Mol. Des..

[41]  J F Davies,et al.  Viracept (nelfinavir mesylate, AG1343): a potent, orally bioavailable inhibitor of HIV-1 protease. , 1997, Journal of medicinal chemistry.

[42]  D. Walters,et al.  Nonpeptidal P2 ligands for HIV protease inhibitors: structure-based design, synthesis, and biological evaluation. , 1996, Journal of medicinal chemistry.

[43]  S. Gulnik,et al.  In vitro anti-human immunodeficiency virus (HIV) activities of transition state mimetic HIV protease inhibitors containing allophenylnorstatine , 1993, Antimicrobial Agents and Chemotherapy.

[44]  D Norbeck,et al.  Characterization of human immunodeficiency virus type 1 variants with increased resistance to a C2-symmetric protease inhibitor , 1994, Journal of virology.

[45]  D. Lamarre,et al.  Second locus involved in human immunodeficiency virus type 1 resistance to protease inhibitors , 1996, Journal of virology.

[46]  L. Bacheler,et al.  DPC 681 and DPC 684: Potent, Selective Inhibitors of Human Immunodeficiency Virus Protease Active against Clinically Relevant Mutant Variants , 2001, Antimicrobial Agents and Chemotherapy.

[47]  H. Lilie,et al.  Synthesis and biological evaluation of first N-alkyl syn dimeric 4-aryl-1,4-dihydropyridines as competitive HIV-1 protease inhibitors. , 2001, European journal of medicinal chemistry.

[48]  A. Hilgeroth,et al.  Synthesis and biological evaluation of the first N-alkyl cage dimeric 4-aryl-1,4-dihydropyridines as novel nonpeptidic HIV-1 protease inhibitors. , 1999, Journal of medicinal chemistry.

[49]  S. Salvadori,et al.  HIV-1 protease inhibitors containing an N-hydroxyamino acid core structure. , 2001, Bioorganic & medicinal chemistry.

[50]  P. Lam,et al.  Cyclic HIV protease inhibitors: design and synthesis of orally bioavailable, pyrazole P2/P2' cyclic ureas with improved potency. , 1998, Journal of medicinal chemistry.

[51]  J. Hulten,et al.  Synthesis and comparative molecular field analysis (CoMFA) of symmetric and nonsymmetric cyclic sulfamide HIV-1 protease inhibitors. , 2001, Journal of medicinal chemistry.

[52]  B. Sadler,et al.  In vitro antiviral activity of 141W94 (VX-478) in combination with other antiretroviral agents. , 1996, Antiviral research.

[53]  R. Darlington,et al.  Factor Analysis , 2008 .

[54]  L. Hall,et al.  The Molecular Connectivity Chi Indexes and Kappa Shape Indexes in Structure‐Property Modeling , 2007 .

[55]  L. Bacheler,et al.  Unsymmetrical cyclic ureas as HIV-1 protease inhibitors: novel biaryl indazoles as P2/P2' substituents. , 1999, Bioorganic & medicinal chemistry letters.

[56]  G. Decrescenzo,et al.  SC-52151, a novel inhibitor of the human immunodeficiency virus protease , 1995, Antimicrobial agents and chemotherapy.

[57]  L. Tong,et al.  Potent HIV protease inhibitors containing a novel (hydroxyethyl)amide isostere. , 1997, Journal of medicinal chemistry.

[58]  K. Fujimoto,et al.  Design and synthesis of a novel series of HIV-1 protease inhibitors. , 1999, Bioorganic & medicinal chemistry.

[59]  P. Darke,et al.  Synthesis and antiviral activity of a series of HIV-1 protease inhibitors with functionality tethered to the P1 or P1' phenyl substituents: X-ray crystal structure assisted design. , 1992, Journal of Medicinal Chemistry.

[60]  A B Smith,et al.  An orally bioavailable pyrrolinone inhibitor of HIV-1 protease: computational analysis and X-ray crystal structure of the enzyme complex. , 1997, Journal of medicinal chemistry.

[61]  P. Jadhav,et al.  Cyclic urea amides: HIV-1 protease inhibitors with low nanomolar potency against both wild type and protease inhibitor resistant mutants of HIV. , 1997, Journal of medicinal chemistry.

[62]  P. Darke,et al.  L-735,524: the design of a potent and orally bioavailable HIV protease inhibitor. , 1994, Journal of medicinal chemistry.

[63]  Chong-Hwan Chang,et al.  Molecular Recognition of Cyclic Urea HIV-1 Protease Inhibitors* , 1998, The Journal of Biological Chemistry.

[64]  W. Han,et al.  Tricyclic ureas: a new class of HIV-1 protease inhibitors. , 1998, Bioorganic & medicinal chemistry letters.

[65]  I. Luque,et al.  Structure-based thermodynamic analysis of HIV-1 protease inhibitors. , 1997, Biochemistry.

[66]  Lemont B. Kier,et al.  The electrotopological state: structure information at the atomic level for molecular graphs , 1991, J. Chem. Inf. Comput. Sci..

[67]  D. Walters,et al.  Potent HIV protease inhibitors incorporating high-affinity P2-ligands and (R)-(hydroxyethylamino)sulfonamide isostere. , 1998, Bioorganic & medicinal chemistry letters.

[68]  D. Walters,et al.  Structure based design: novel spirocyclic ethers as nonpeptidal P2-ligands for HIV protease inhibitors. , 1998, Bioorganic & medicinal chemistry letters.

[69]  HIV protease inhibitory bis-benzamide cyclic ureas: a quantitative structure-activity relationship analysis. , 1996, Journal of medicinal chemistry.

[70]  Amos B. Smith,et al.  Structure-based design and synthesis of HIV-1 protease inhibitors employing beta-D-mannopyranoside scaffolds. , 2002, Bioorganic & medicinal chemistry letters.