In silico Methods for Design of Kinase Inhibitors as Anticancer Drugs

Abstract

Rational drug design implies usage of molecular modeling techniques such as pharmacophore modeling, molecular dynamics, virtual screening, and molecular docking to explain the activity of biomolecules, define molecular determinants for interaction with the drug target, and design more efficient drug candidates. Kinases play an essential role in cell function and therefore are extensively studied targets in drug design and discovery. Kinase inhibitors are clinically very important and widely used antineoplastic drugs. In this review, computational methods used in rational drug design of kinase inhibitors are discussed and compared, considering some representative case studies.

Keywords: drug discovery; kinase inhibitors; molecular modeling; pharmacophore; rational drug design.

Figure 1

Structures of selected protein kinase inhibitors that have been approved for clinical use.

Figure 2

The crystal structure of imatinib-bound form of the Abl kinase (PDB accession code: 2HYY), colored as rainbow from N-lobe (blue) to C-lobe (red). Imatinib is represented as ball and stick.

Figure 3

Diversity of allosteric binding pockets in different protein kinases. (A) ABL kinase in complex with fragment FRAG1 (PDB: 3MS9) (Jahnke et al., 2010); (B) CDK2 in complex with 2 molecules of 8-anilino-1-naphthalene sulfonic acid (PBD: 4EZ7) (Martin et al., 2012); (C) CHK1 bound to allosteric inhibitor (1S)-1-(1H-benzimidazol-2-yl)ethyl (3,4-dichlorophenyl)carbamate (PDB: 3JVR) (Vanderpool et al., 2009); (D) EGFR in complex with Mig6 protein (PDB: 4R3P) (Park et al., 2015); (E) PDK1 with PIF pocket inhibitor RF4 (Rettenmaier et al., 2015); (F) MEK1 in complex with 5-bromo-N-(2,3-dihydroxyprpoxy)-3,4-difluoro-2-[(2fluoro-4-iodophenyl)amino]benzamide (PDB: 1S9J) (Ohren et al., 2004); (G) Sequence alignment of these kinases showing which amino acids are involved in the binding of allosteric modulators.

Figure 4

Examples of inactive and active conformations of epidermal growth factor receptor (EGFR) kinase (PDB accession codes: 4HJO and 2GS6, respectively), and their superimposition. The activation loop of inactive conformation (purple) is closed therefore blocking the substrate to enter catalytic loop, while activation loop in active conformation (turquoise) is opened allowing the ATP to bind.

Figure 5

Crystal structures of p38 mitrogen-activated protein (MAP) kinase with imidazo[4,5-b]pyridin-2-one derivatives. (A) Lead compound found by HTS (PDB: 6M95). (B) Potent p38 MAP kinase inhibitor designed using structure-based drug design (SBDD) approach (PDB: 6M9L).

Figure 6

Crystal structures of initial screening hits for inhibitors of the vascular endothelial growth factor (VEGF) that lead to the discovery of pazopanib. (A) PDB: 1Y6A, (B) PDB: 1Y6B.

Figure 7

(A) Presentation of the identified scaffolds by in vitro biochemical screening as PI3K inhibitors (hinge interacting moieties are labeled in red), Ar—presents carbocyclic or heterocyclic aromatic rings; (B) the scheme of lead optimization of the selected morpholine derivatives.

Figure 8

(A) Crystal structure of MNK-2 complexed with staurosporine (PDB: 2HW7); the atoms of the substructure used in the study of pharmacophore fitting screening are labeled in green; (B) the lead optimization strategies starting from fragment ET-38766 to clinical candidate ETC-206.

Figure 9

Discovery of Asciminib (Schoepfer et al., 2018). (A) Representation of initial hypothesis regarding bending of helix I (orange). Assembled inactive state of ABL1 kinase in complex with myristic acid (orange sticks) (PDB: 1OPL, SH3, and SH2 domains omitted for clarity) is superimposed on ABL1 in complex with fragment 2 (green sticks) (PDB: 3MS9). Steric clash between isoleucin I521 (orange sticks) on helix I and fragment 2 prevents full bending of helix I and formation of assembled inactive state of ABL1. Helix I is not visible in the PDB: 3MS9. (B) Medicinal chemistry progression from fragment 2 to fragment derived hit 4, first active hit–compound 5 and finally clinical candidate—Asciminib.