Colorectal cancer is considered one of the leading causes of death that is linked with the Kirsten Rat Sarcoma (KRAS) harboring codons 13 and 61 mutations. The objective for this study is to search for clinically important codon 61 mutations and analyze how they affect the protein structural dynamics. Additionally, a deep-learning approach is used to carry out a similarity search for potential compounds that might have a comparatively better affinity. Public databases like The Cancer Genome Atlas and Genomic Data Commons were accessed for obtaining the data regarding mutations that are associated with colon cancer. Multiple analysis such as genomic alteration landscape, survival analysis, and systems biology-based kinetic simulations were carried out to predict dynamic changes for the selected mutations. Additionally, a molecular dynamics simulation of 100 ns for all the seven shortlisted codon 61 mutations have been conducted, which revealed noticeable deviations. Finally, the deep learning-based predicted compounds were docked with the KRAS 3D conformer, showing better affinity and good docking scores as compared to the already existing drugs. Taking together the outcomes of systems biology and molecular dynamics, it is observed that the reported mutations in the SII region are highly detrimental as they have an immense impact on the protein sensitive sites' native conformation and overall stability. The drugs reported in this study show increased performance and are encouraged to be used for further evaluation regarding the situation that ascends as a result of KRAS mutations.