title: Lead identification for the K-Ras protein: virtual screening and combinatorial fragment-based approaches.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: 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.
authors.forename: Akbar Ali Khan
authors.initials: AA
authors.lastname: Pathan
authors.affiliation: Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Hajipur, India.
authors.forename: Bhavana
authors.initials: B
authors.lastname: Panthi
authors.affiliation: Genome Research Chair (GRC), Department of Biochemistry, College of Science, King Saud University, Kingdom of Saudi Arabia.
authors.forename: Zahid
authors.initials: Z
authors.lastname: Khan
authors.affiliation: 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.
authors.forename: Purushotham Reddy
authors.initials: PR
authors.lastname: Koppula
authors.affiliation: Genome Research Chair (GRC), Department of Biochemistry, College of Science, King Saud University, Kingdom of Saudi Arabia.
authors.forename: Mohammed Saud
authors.initials: MS
authors.lastname: Alanazi
authors.affiliation: Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Hajipur, India.
authors.lastname: Sachchidanand
authors.affiliation: Genome Research Chair (GRC), Department of Biochemistry, College of Science, King Saud University, Kingdom of Saudi Arabia.
authors.forename: Narasimha Reddy
authors.initials: NR
authors.lastname: Parine
authors.affiliation: Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Hajipur, India.
authors.forename: Mukesh
authors.initials: M
authors.lastname: Chourasia
keywords: K-Ras; antitumor agent; molecular docking; molecular modeling; virtual screening