Investigating Drug-Mediated Conformational Changes in KRas

Mohanty, Saswat Kumar (2022) Investigating Drug-Mediated Conformational Changes in KRas. Masters thesis, Indian Institute of Science Education and Research Kolkata.

Text (MS dissertation of Saswat Kumar Mohanty (17MS204)) 17MS204_Thesis_file.pdf - Submitted Version Restricted to Repository staff only Download (9MB)

Abstract

Intrinsically Disorder Proteins (IDPs) are a significant part of the human proteome, and their involvement in numerous diseases is well documented. As IDPs have no single fixed structure, they represent an exception to the structured-protein concept, known as Anfinsen’s dogma. On the other hand, there are Intrinsically Disorder Regions (IDRs) in some protein structures that can be fully or partially disordered, containing highly charged amino acid residues. Despite their unstructured regions, they are involved in critical roles in cellular functioning. KRas, a member of the Ras GTPase family, is one of such proteins containing a number of IDRs known as switch regions. Mutations in wild-type KRas at the G12 position cause loss of GTPase activity and acquire oncogenic properties that result in tumour cell growth and cancer progression. Recently, AMG510 was one of the first KRas (G12C) inhibitors efficacious against KRas G12C tumors. However, a recent FDA-approved drug MRTX849 is more efficacious than AMG510 in tumour regression in KRas G12C mutant cell lines of multiple tumour types, especially patients with lung and colon cancer patients. As acquired resistance to the mutant selective KRas G12C inhibitor like AMG510 is a major concern in lung cancer, to understand different druginduced structural changes of KRas, this thesis work attempts to perform computational studies on the G12C mutated KRas, as well as the above two drug bound forms: AMG-510 and MRTX-849. This thesis contains four chapters as follows: Chapter-I contains introduction to IDPs/IDRs, the structural plasticity and the experimental and computational methods to characterise their properties. We refresh through the computational methods, in chapter-II, which we have used to run our molecular dynamics simulations and which we have used to extract meaningful data from our trajectories. Through our analysis of fluctuation, contact and correlation map, in chapter-III, we find that MRTX is potent in inhibiting the fluctuation of the IDR switches as compared to AMG. MRTX forms a large number of hydrogen and a few hydrophobic interactions with the Switch-II loop. In chapter-IV, our thorough free energy analyses and comparison of drug-bound and unbound forms of KRas explore all possible druginduced conformational states. This exploration indicates that MRTX is likely to restrict the GDP-GTP exchange in its functional cycle, and hence, possible this is one of the reasons that may exert high efficacy. This study also predicts that switch-II inhibition can act as a potent target for any future drug to make KRas-G12C inhibition operational and devoid of acquired drug-resistance.

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