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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

1
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.
2
Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Hajipur, India.
3
Genome Research Chair (GRC), Department of Biochemistry, College of Science, King Saud University, Kingdom of Saudi Arabia.
4
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.

Abstract

OBJECTIVE:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSION:

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.

KEYWORDS:

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

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