Most state-of-the-art in silico design methods fail due to misfolding of designed sequences to a conformation other than the target. Thus, a method to design misfolding resistant proteins will provide a better understanding of the misfolding phenomenon and will also increase the success rate of in silico design methods. In this work, we optimize the conformational ensemble to be selected for negative design purposes based on the similarity of the conformational ensemble to the target. Five ensembles with different degrees of similarity to the target are created and destabilized and the target is stabilized while designing sequences using mean field theory and Monte Carlo simulation methods. The results suggest that the degree of similarity of the non-native conformations to the target plays a prominent role in designing misfolding resistant protein sequences. The design procedures that destabilize the conformational ensemble with moderate similarity to the target have proven to be more promising. Incorporation of either highly similar or highly dissimilar conformations to the target conformation into the non-native ensemble to be destabilized may lead to sequences with a higher misfolding propensity. This will significantly reduce the conformational space to be considered in any protein design procedure. Interestingly, the results suggest that a sequence with higher frustration in the target structure does not necessarily lead to a misfold prone sequence. A successful design method may purposefully choose a frustrated sequence in the target conformation if that sequence is even more frustrated in the competing non-native conformations.