title: A method for computational combinatorial peptide design of inhibitors of Ras protein.
abstract: A computational combinatorial approach is proposed for the design of a peptide inhibitor of Ras protein. The procedure involves three steps. First, a 'Multiple Copy Simultaneous Search' identifies the location of specific functional groups on the Ras surface. This search method allowed us to identify an important binding surface consisting of two beta strands (residues 5-8 and 52-56), in addition to the well known Ras effector loop and switch II region. The two beta strands had not previously been reported to be involved in Ras-Raf interaction. Second, after constructing the peptide inhibitor chain based on the location of N-methylacetamide (NMA) minima, functional groups are selected and connected to the main chain Calpha atom. This step generates a number of possible peptides with different sequences on the Ras surface. Third, potential inhibitors are designed based on a sequence alignment of the peptides generated in the second step. This computational approach reproduces the conserved pattern of hydrophobic, hydrophilic and charged amino acids identified from the Ras effectors. The advantages and limitations of this approach are discussed.
authors.affiliation: Ludwig Institute for Cancer Research and Cooperative Research Centre for Cellular Growth Factors, P.O. Box 2008, Royal Melbourne Hospital, Parkville, VIC 3050, Australia. jun.zheng@ludwig.edu.au
authors.forename: J
authors.initials: J
authors.lastname: Zeng
authors.forename: H R
authors.initials: HR
authors.lastname: Treutlein
mesh_terms: D000081:Acetamides / Q000737:chemistry; D015195:Drug Design; D006801:Humans; D008958:Models, Molecular; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D012984:Software; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D000081:Acetamides; D019151:Peptide Library; D010455:Peptides; C011080:polyglycine; D018631:ras Proteins; C018595:N-methylacetamide