Structure-based design of protein kinase inhibitors

Posted by beauty33 on October 29th, 2021

Protein kinases are effective anti-cancer drug targets that have been proven in many experiments and facts. Many small molecule protein kinase inhibitors approved by the FDA can be used for cancer treatment. The effectiveness of kinases as targets for other diseases, including neurological disorders, inflammation and metabolic diseases, is also being tested. Human protein kinase consists of more than 500 kinases. Human protein kinases are responsible for the chemical process of phosphorylating hydroxyl receptors in the amino acid residues of substrate proteins (serine, threonine and tyrosine) and for regulating intracellular signalling processes, such as cell growth, differentiation and apoptosis. In turn, abnormal kinase activity can trigger inappropriate signalling and uncontrolled cell growth, which can lead to a variety of diseases, particularly cancer. Therefore, small molecule kinase inhibitors have great potential for new drug of research and development.

Active region of protein kinases

Most kinases are composed of at least two structural domains, a catalytic domain, which binds and phosphorylates the substrate protein, and a regulatory domain, which interacts directly with an auxiliary protein to regulate the catalytic activity of the catalytic domain by changing its conformation. The core structure of the catalytic region is made up of a small N-terminal region and a large C-terminal region, which are connected by a hinge region. The N-terminal region is mainly composed of multiple β-segments folded, while the C-terminal region mainly consists of a-helices, and the ATP-binding region is located between the N-terminal and C-terminal regions.

Design strategies for protein kinase inhibitors

Structure-based molecular design has been prominent in the development history of various FDA-approved small molecule protein kinase inhibitors. Since the first crystal structure of protein kinase A (PKA) was reported in 1991, more than 1000 X-ray crystal structures have been reported, most of which are high-resolution.

Several more representative FDA-approved marketed drugs contain hinge-bound heterocyclic backbones, many of which have been used to design highly active inhibitors of multiple target kinases, including VEGFR, Kit, B-Raf, EGFR, KDR, etc. The majority of lead compounds for small molecule kinase inhibitors can be obtained by high-throughput screening, virtual screening or fragment-based screening.

Kinase inhibitors can be divided into three categories according to their binding sites: the first category of kinase inhibitors act on the ATP binding site; the second category of kinase inhibitors act on the regulatory region; and the third category of kinase inhibitors also known as allosteric inhibitors, which target hydrophobic pockets away from the ATP binding site, but can modulate kinase activity by causing conformational changes in the ATP binding pocket.

The first type of kinase inhibitor design

The first type of inhibitor possesses a heterocyclic backbone that can occupy the nucleoside binding region. Similar to the nucleoside in the ATP molecule, this heterocyclic backbone can also form three hydrogen bonds with the hinge region. Optimisation of inhibitors can extend the interaction of molecules with adjacent hydrophobic pockets by means of groups. Dasatinib is the first type of kinase inhibitor designed from the lead compound of thiazole.

The second type of kinase inhibitor design

Similar to the first type of inhibitor, the second type of kinase inhibitor binds to the ATP-binding site in the kinase, but this type of inhibitor can extend the interaction to the allosteric site, which can only be utilized when the kinase is inactive. Imatinib, Nilotinib and Sorafenib, which are currently approved for marketing as class II inhibitors, have been successful in inhibiting this effect.

Allosteric inhibitor design

Allosteric kinase inhibitors are also commonly referred to as type III kinase inhibitors. They can bind to the kinase inhibitor allosteric site (a region that is not an ATP-binding site), and regulate the binding of the ATP molecule to the kinase by inducing conformational changes in the kinase, thereby rendering the kinase inactive. Because these molecules bind to the specific sites in the kinase, allosteric kinase inhibitors have the best selectivity.

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