CONCEPTS: New dynamic algorithm for de novo drug suggestion

We describe a new method for de novo design of molecules that bind to protein active sites. The method, CONCEPTS (Creation of Novel Compounds by Evaluation of Particles at Target Sites), places a group of atom‐like particles in the site. The particles are free to move within the site to improve binding to the protein. A key innovation of this technique is that covalent connections are made among the particles in a stochastic and dynamically reversible manner. These changes in the topology are either accepted or rejected depending on their ability to improve the total energy of the enzyme–inhibitor complex. The method is applied to two test systems: The FK506 binding protein (FKBP‐12) and HIV‐1 aspartyl protease. In both cases, we are able to predict, de novo, drugs that have striking similarities to known potent inhibitors and that can successfully be used to generate “hits” of the known inhibitors from a data base. © John Wiley & Sons, Inc.

[1]  P. Kollman,et al.  An all atom force field for simulations of proteins and nucleic acids , 1986, Journal of computational chemistry.

[2]  J. Banavar,et al.  Computer Simulation of Liquids , 1988 .

[3]  Conrad C. Huang,et al.  Automated site-directed drug design using molecular lattices , 1992 .

[4]  I. Kuntz,et al.  Docking flexible ligands to macromolecular receptors by molecular shape. , 1986, Journal of medicinal chemistry.

[5]  J M Blaney,et al.  A geometric approach to macromolecule-ligand interactions. , 1982, Journal of molecular biology.

[6]  R. Wade,et al.  New hydrogen-bond potentials for use in determining energetically favorable binding sites on molecules of known structure. , 1989, Journal of medicinal chemistry.

[7]  Akiko Itai,et al.  Automatic creation of drug candidate structures based on receptor structure. Starting point for artificial lead generation , 1991 .

[8]  E A Emini,et al.  Benzocycloalkyl amines as novel C-termini for HIV protease inhibitors. , 1991, Journal of medicinal chemistry.

[9]  I. Kuntz,et al.  Using shape complementarity as an initial screen in designing ligands for a receptor binding site of known three-dimensional structure. , 1988, Journal of medicinal chemistry.

[10]  R F Standaert,et al.  Atomic structure of FKBP-FK506, an immunophilin-immunosuppressant complex , 1991, Science.

[11]  J. Huff,et al.  HIV protease: a novel chemotherapeutic target for AIDS. , 1991, Journal of medicinal chemistry.

[12]  S. Fesik,et al.  NMR studies of molecular complexes as a tool in drug design. , 1991, Journal of medicinal chemistry.

[13]  I. Kuntz,et al.  Conformational analysis of flexible ligands in macromolecular receptor sites , 1992 .

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

[15]  Brian W. Metcalf,et al.  Human immunodeficiency virus protease: A target for aids therapy , 1990 .

[16]  P. Goodford.  A computational procedure for determining energetically favorable binding sites on biologically important macromolecules. , 1985, Journal of medicinal chemistry.

[17]  Stuart L. Schreiber,et al.  Atomic Structure of the Rapamycin Human Immunophilin FKBP-12 Complex , 1991 .

[18]  U. Singh,et al.  A NEW FORCE FIELD FOR MOLECULAR MECHANICAL SIMULATION OF NUCLEIC ACIDS AND PROTEINS , 1984 .

[19]  A M Gronenborn,et al.  Structures of larger proteins in solution: three- and four-dimensional heteronuclear NMR spectroscopy. , 1991, Science.

[20]  A. Brunger.  Free R value: a novel statistical quantity for assessing the accuracy of crystal structures. , 1992 .

[21]  J Moult,et al.  Docking by least-squares fitting of molecular surface patterns. , 1992, Journal of molecular biology.

[22]  J M Thornton,et al.  A novel method for the modelling of peptide ligands to their receptors. , 1991, Protein engineering.

[23]  S. Vasavanonda,et al.  Structure-based, C2 symmetric inhibitors of HIV protease. , 1990, Journal of medicinal chemistry.

[24]  M. Karplus,et al.  Crystallographic R Factor Refinement by Molecular Dynamics , 1987, Science.

[25]  J. Markley,et al.  Two-dimensional nuclear magnetic resonance spectroscopy of proteins: an overview. , 1989, Methods in enzymology.