Molecular docking analysis of KRAS inhibitors for cancer management

Abstract

The majority of human tumors are characterized by abnormal signaling caused by oncogenic RAS proteins. KRAS is a member of the RAS family and is currently one of the most thoroughly researched targets for cancer treatment due to its prevalence in a variety of deadly malignancies. Targeting the KRAS protein, which plays a crucial role in regulating cell growth, differentiation, and apoptosis, shows great potential as a strategy for fighting cancer. Herein, in silico screening of 530 natural compounds against KRAS protein was performed. The top-scoring hits, namely ZINC32502206, ZINC98363763, ZINC85645815, and ZINC98364259 displayed a robust affinity towards KRAS as evidenced by their respective binding affinity values of -10.50, -10.01, -9.80, and -9.70 kcal/mol, respectively which were notably higher than that of the control compound AMG 510 (-9.10 kcal/mol). Through virtual screening and visual inspection, it was observed that these hits effectively interacted with the essential residues located within the active site of KRAS. Based on the findings of this study, it can be inferred that these compounds may have the potential to be employed in the treatment of cancer by targeting KRAS.

Keywords: Cancer; KRAS; inhibitors; natural compounds; virtual screening.

Figure 1

Superimposed binding mode of X-ray-bound AMG 510 (green) and re-docked AMG 510 (blue) with KRAS protein.

Figure 2

3D visualization of screened compounds in the active pocket of KRAS.

Figure 3

Interacting residues of KRAS protein with ZINC98364259 (A), ZINC98363763 (B), ZINC32502206 (C), ZINC85645815 (D), and AMG 510 (E)