Send to

Choose Destination
Onco Targets Ther. 2016 May 2;9:2575-84. doi: 10.2147/OTT.S99671. eCollection 2016.

Lead identification for the K-Ras protein: virtual screening and combinatorial fragment-based approaches.

Author information

Genome Research Chair (GRC), Department of Biochemistry, College of Science, King Saud University, Kingdom of Saudi Arabia; Integrated Gulf Biosystems, Riyadh, Kingdom of Saudi Arabia.
Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Hajipur, India.
Genome Research Chair (GRC), Department of Biochemistry, College of Science, King Saud University, Kingdom of Saudi Arabia.
Department of Internal Medicine, School of Medicine, Columbia, MO, USA; Harry S. Truman Memorial Veterans Affairs Hospital, School of Medicine, Columbia, MO, USA; Department of Radiology, School of Medicine, Columbia, MO, USA.



Kirsten rat sarcoma (K-Ras) protein is a member of Ras family belonging to the small guanosine triphosphatases superfamily. The members of this family share a conserved structure and biochemical properties, acting as binary molecular switches. The guanosine triphosphate-bound active K-Ras interacts with a range of effectors, resulting in the stimulation of downstream signaling pathways regulating cell proliferation, differentiation, and apoptosis. Efforts to target K-Ras have been unsuccessful until now, placing it among high-value molecules against which developing a therapy would have an enormous impact. K-Ras transduces signals when it binds to guanosine triphosphate by directly binding to downstream effector proteins, but in case of guanosine diphosphate-bound conformation, these interactions get disrupted.


In the present study, we targeted the nucleotide-binding site in the "on" and "off" state conformations of the K-Ras protein to find out suitable lead compounds. A structure-based virtual screening approach has been used to screen compounds from different databases, followed by a combinatorial fragment-based approach to design the apposite lead for the K-Ras protein.


Interestingly, the designed compounds exhibit a binding preference for the "off" state over "on" state conformation of K-Ras protein. Moreover, the designed compounds' interactions are similar to guanosine diphosphate and, thus, could presumably act as a potential lead for K-Ras. The predicted drug-likeness properties of these compounds suggest that these compounds follow the Lipinski's rule of five and have tolerable absorption, distribution, metabolism, excretion and toxicity values.


Thus, through the current study, we propose targeting only "off" state conformations as a promising strategy for the design of reversible inhibitors to pharmacologically inhibit distinct conformations of K-Ras protein.


K-Ras; antitumor agent; molecular docking; molecular modeling; virtual screening

Supplemental Content

Full text links

Icon for Dove Medical Press Icon for PubMed Central
Loading ...
Support Center