Exploring the Lapse in Druggability: Sequence Analysis, Structural Dynamics and Binding Site Characterization of K-RasG12C Variant, a Feasible Oncotherapeutics Target

Abstract

Background: The difficulty in druggability of K-Ras variant has presented a challenge in the treatment of cancer diseases associated with its dysfunctionality. Despite the identification of different binding sites, limited information exists in the literature about their characteristics. Therefore, identification, crossvalidation and characterization of its druggable sites would aid the design of chemical compounds that will arrest its dysfunctionality related oncogenesis. Objective: This study entails the identification, cross-validation and characterization of K-Ras G12C variant’s binding sites for potential druggability, coupled with the elucidation of alterations in 3D conformations and dynamics. Method: Molecular dynamics simulation was carried out on the inactive, the active and the hyperactive K-RasG12Cvariant using the amber software package. The SiteMap software was employed in identifying and characterizing the druggable binding sites while the validation of the binding sites was carried out with the SiteHound and MetaPocket servers. Results: Four druggable binding sites were identified, validated and characterized based on physicochemical attributes such as size, volume, degree of enclosure or exposure, degree of contact, hydrophobic/hydrophilic character, hydrophobic/hydrophilic balance and hydrogen-bonding features. Conformational studies also revealed that the K-Ras variant exhibited notable structural instability, increased flexibility and a strongly anticorrelated movement compared to the inactive and active wildtype forms. Conclusion: The attributes of the characterized druggable sites will be useful in designing site-specific K-Ras inhibitors for the treatment of K-Ras variant associated cancer diseases.