Protein Kinase Inhibitors: Structural Insights Into Selectivity

Thaimattam, Ram; Banerjee, Rahul; Miglani, Rajni; Iqbal, Javed

doi:10.2174/138161207781757042

Cited by 50 publications

(43 citation statements)

References 85 publications

(129 reference statements)

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“…X-ray structural analyses revealed the presence of an extensive network of a salt bridge (Arg166--Asp200) and hydrophobic interactions (Leu164, Leu193, Tyr198 and Phe201) between the A-loop and the C-loop, and the hydrogen bonds (Leu192-Tyr198, Lys194-Val197) inside the A-loop are crucial for opening the ATP binding pocket and stabilizing the active conformation [52]. The structures of the ATP binding pockets in protein kinases are quite similar, and thus the development of a highly selective drug is difficult [55][56][57]. Protein kinases commonly form two hydrogen bonds with the ATP adenine through the residues in the hinge region, while Pim1 forms only one hydrogen bond, between the N6 atom of the ATP adenine ring and the backbone carbonyl oxygen atom of the first hinge residue (Glu121) ( Figure 2B) [50][51][52].…”

Section: Structural Features Of Pim1mentioning

confidence: 99%

Insights from Pim1 structure for anti-cancer drug design

Ogawa

Yuki

Tanaka

2012

Expert Opinion on Drug Discovery

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To obtain a potent and selective Pim1 inhibitor as a lead compound, the authors propose the development of compounds which simultaneously interact with both the ATP binding site (Lys67, Glu121 and Phe49) and substrate binding residues (Asp128, Asp131 and Glu171). The development of Pim1 inhibitors could lead to new therapeutic options for a number of hematological malignancies and prostate cancer in the future.

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Section: Structural Features Of Pim1mentioning

confidence: 99%

Insights from Pim1 structure for anti-cancer drug design

Ogawa

Yuki

Tanaka

2012

Expert Opinion on Drug Discovery

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“…This section deals with substrate recognition by protein kinases. The eukaryotic kinases contain a catalytic region consisting of approximately 250 amino acid residues comprising an N-terminal domain of b-sheets and a C-terminal domain of a-helices [224][225][226][227][228][229][230][231][232][233][234][235]. The phosphoryl donor, ATP, binds in a cleft between the two domains such that the hydrophobic pocket is able to accommodate the adenosine moiety with the phosphate backbone oriented towards the enzyme surface.…”

Section: Protein Kinasesmentioning

confidence: 99%

Substrate Recognition

Brocklehurst

Gul

Pickersgill

2009

Amino Acids, Peptides and Proteins in Organic Chemistry

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Specific molecular recognition processes by which molecules recognize and discriminate between closely related partners are involved in essentially all aspects of biological function, ranging in complexity from enzyme-inhibitor and enzymesubstrate systems to phenomena such as gene expression, the immune system, and synaptic transmission, and these are important considerations in drug design [1]. This chapter is concerned with general concepts exemplified by a selection of relatively well-defined enzyme-substrate and, by extension, enzyme-inhibitor systems. The original concept of recognition by complementarity in the enzymesubstrate adsorptive (Michaelis) complex was suggested by Emil Fischer in 1894 using his well-known lock-and-key analogy [2]. It is now generally accepted that this has now been superseded by complementarity in the reaction transition state, based on the ideas reported by J.B.S. Haldane [3] in 1930 and elaborated by Linus Pauling [4] in 1946. The catalytic potential of enzymes derives from stabilization in the transition state relative to any stabilization in the Michaelis complex. The latter is anticatalytic in that the free energy expended in stabilizing the adsorptive complex offsets the transition-state stabilization energy (e.g., [5]).Valuable chapters and books on enzyme catalysis and inhibition are available (e.g., [5][6][7][8][9][10][11]) and detailed mechanistic studies on many individual enzymes are described in Sinnot [12]. Macromolecular catalysis includes also catalysis by catalytic antibodies [13] and by synthetic polymers [14], including molecularly imprinted polymers [15]. The contributions of selections of various types of chemical catalysis such as acid-base, nucleophilic, and electrophilic catalysis [5,6,8] are almost always insufficient to account for the high catalytic efficiency of enzymes. A particularly important additional contribution is the entropic advantage that derives from the fact that enzyme catalysis occurs within an enzyme-substrate complex. The complex is essentially a single molecular species and the catalytic act involves one or more unimolecular steps during which there is no loss of translational or rotational entropy

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“…It was thought to be impossible to identify selective and potent adenosine triphosphate (ATP) competitive inhibitors in view of both the conservation of the ATP-binding domain and the high ATP concentration present in cells. Today, nanomolar selective inhibitors are available 1,2 . The first inhibitors were designed to inhibit protein kinases in their active form.…”

Section: Introductionmentioning

confidence: 99%