Kiralj R., Ferreira M.M.C., “A STUDY OF HIV-1 PROTEASE – INHIBITOR INTERMOLECULAR INTERACTIONS BY USING QUANTITATIVE MOLECULAR GRAPHICS AND A PRIORI QSAR”. Caxambu, MG, Brazil, 11-16/11/2001: 1º Simpósio Brasileiro em Química Medicinal, QSAR e Modelagem Molecular: Novas Estratégias em Planejamento Racional de Fármacos [1st Brazilian Symposium on Medicinal Chemistry, QSAR and Molecular Modeling: New Approaches in Drug Design]. Poster APM21. Section: 4. Applications of Multivariate QSAR.

Name
      Rudolf Kiralj

Institution/Company
      Instituto de Química, Universidade Estadual de Campinas

Country
      Brasil

Second Abstract Title
      A STUDY OF HIV-1 PROTEASE - INHIBITOR INTERMOLECULAR INTERACTIONS BY USING QUANTITATIVE
      MOLECULAR GRAPHICS AND A PRIORI QSAR

Second Abstract
     A STUDY OF HIV-1 PROTEASE - INHIBITOR INTERMOLECULAR INTERACTIONS BY USING QUANTITATIVE
     MOLECULAR GRAPHICS AND A PRIORI QSAR

     R. Kiralj, M. M. C. Ferreira, Instituto de Química, Universidade Estadual de Campinas, Campinas, SP, 13083-970, Brazil
     Keywords: HIV-1 Protease - inhbitor intermolecular interaction.

     Although peptidic HIV-1 protease inhibitirs were studied by sophisticated¹ and simple² QSARs, and crystal structures
     of some protease-inhibitor coplexes are known,³ some aspects of protease-inhibitor intermolecular interactions were
     not considered. Molecular graphics is usually utilized as a visualization aid. In this work we employ molecular graphics
     on inhibitor L-700,417 as a quantitative tool. Molecular dimensions (like geometrical parameters),parameters of
     electron density and frontier orbital isosurfaces were measured/calculated from high quality pictures by an empirical
     method. The relationships between enzyme-inhibitor geometry and inhibitor electron density distribution, beyond
     van der Waals radii, were established. Another empirical method and Partial Least Squares (PLS) with a priori
     molecular descriptors² were used to predict activities of L-700,417 derivatives. These activities were well related to
     enzyme-inhibitor interaction energy and inhibitor molecular properties. The group additivity of activities was confirmed.
     A priori QSAR included modeling of L-700,417 derivatives at the active site of frozen enzyme. The number and size of
     substituents, especially number of hydroxyl groups, and the presence of various hydrophobic hooks attached to a
     substituent significantly chages the inhibitor hydrophobicity, its biological activity and the enzyme-inhibitor interaction
     energy.

     1 Pérez, C.; Pastor, M.; Ortiz, A. R.; Gago, F. J. Med. Chem. 41 (1998) 836.
     2 Kiralj, R.; Ferreira, M. M. C. J. Mol. Graph. submitted for publication.
     3 Database for Anti-HIV Compounds. National Institute for Allergy and Infectious Deseases, Bethesda, Maryland, US.
     http://www.niaid.nih.gov/daids/dtpdb/

     FAPESP