Exploring the lapse in druggability: Sequence Analysis, Structural Dynamics and binding site characterization of K-RasG12C variant, a feasible oncotherapeutics target.

The difficulty in druggability has presented a hurdle in the treatment of cancer diseases associated with dysfunctional mutant K-ras. This has so far impeded the emergence of suitable inhibitors to discontinue its aberrant activities. Despite the identification of different interactive sites, limited information exists in literature about their characteristics that could aid the design and development of appropriate inhibitors that could bind at its catalytic or effector binding sites, thereby disrupting oncogenic activities. While binding of inhibitors at the K-ras catalytic site could alter activity switch, targeting effector binding regions would disrupt its association with effector proteins such as Raf. Moreover, identification and cross validation of druggable sites on mutant K-ras coupled with characterization would aid the design of characteristic chemical compounds for such sites. Herein, we carried out a comprehensive study of K-ras G12C mutant to identify, cross-validate and characterize its binding sites for potential druggability, coupled with the elucidation of alterations in 3D conformations and dynamics. From our results, the identified druggable sites were selected based on cross-validation and were characterized based on site attributes to provide insights for suitable ligands. Conformational studies revealed that the mutant exhibited notable structural instability, increased flexibility and a strongly anti-correlated movement compared to the inactive and active wildtype forms. Furthermore, identified druggable sites served as the basis of defining lead compounds with nucleophilic and electrophilic attributes for each site. These findings will contribute to the development of site-specific K-ras inhibitors for the treatment of cancer diseases associated with oncogenic K-ras activities.