Conformational Analyses and MO Studies of f152A1 and Its Analogues as Potent Protein Kinase Inhibitors

• Published in: Journal of chemical information and modeling Vol. 49; no. 12; pp. 2650 - 2659
• Main Authors: Ikemori-Kawada, Megumi, Kawai, Takatoshi, Goto, Masaki, Wang, Yuan John, Kawakami, Yoshiyuki
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 28.12.2009
• Subjects: Adenosine triphosphatase; Amino Acid Sequence; Binding sites; Chemical compounds; Chemical Information; Chemical synthesis; Drug Discovery; Humans; Hydroxides - chemistry; Kinases; Lactones - chemistry; Lactones - pharmacology; MAP Kinase Kinase 1 - antagonists & inhibitors; MAP Kinase Kinase 1 - chemistry; Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 1 - chemistry; Models, Molecular; Molecular Conformation; Molecular Sequence Data; Molecular structure; Protein Kinase Inhibitors - analogs & derivatives; Protein Kinase Inhibitors - chemistry; Protein Kinase Inhibitors - pharmacology; Proteins; Stereoisomerism; Temperature
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/ci9003128

f152A1 was isolated from a fermentation broth of Curvularia verruculosa and characterized as a potent inhibitor of TNFα transcription, with anti-inflammatory activity. f152A1 and several analogues displayed inhibitory activity against the MAP kinases ERK2 and MEK1 in in vitro kinase assays. Through SAR studies on f152A1 and analogues prepared via total synthesis, we have identified structural features that contribute to inhibitory activity. To rationalize these results and to aid in the discovery process, a combination of high temperature molecular dynamics and MOPAC AM1 semiempirical molecular orbital method studies was used in studies that yielded a postulated active conformation, M1(8). This active conformation M1(8) reflects a high degree of conformational similarity among f152A1 and its more potent analogues. In view of the highly reactive cis-enone moiety in the flexible 14-membered resorcylic acid lactone ring of f152A1, the chemical reactivities of the enone moieties in various analogues were assessed by molecular orbital calculations. The enone reactivity analyses suggested that these inhibitors were prone to Michael addition at the α,β-unsaturated ketone moiety and might chemically react with cysteine residues in the ATP-binding site of MAP kinases. Reactivity of the cis-enone moiety and the M1(8) conformation make important contributions to the inhibitory activity of MAP kinases.