Non-structural protein (NS1) is a 350 amino acid long conserved protein in the dengue virus. Conservation of NS1 is expected due to its importance in dengue pathogenesis. The protein is known to exist in dimeric and hexameric states. The dimeric state is involved in its interaction with host proteins and viral replication, whereas the hexameric state is involved in viral invasion. In this work, we performed extensive structure and sequence analysis of NS1 protein, and uncovered the role of NS1 quaternary states in its evolution. A three-dimensional modeling of unresolved loop regions in NS1 structure is performed. 'Conserved' and 'Variable' regions within NS1 protein were identified from sequences obtained from patient samples and the role of compensatory mutations in selecting destabilizing mutations was identified. Molecular dynamics (MD) simulations were performed to extensively study the effect of a few mutations on NS1 structure stability and study compensatory mutations. Virtual saturation mutagenesis, predicting the effect of every individual amino acid substitution on NS1 stability sequentially, revealed virtual-conserved and variable sites. The increase in number of observed and virtual conserved regions across NS1 quaternary states suggests the role of higher order structure formation in its evolutionary conservation. Our sequence and structure analysis could enable in identifying possible protein-protein interfaces and druggable sites. Virtual screening of nearly 10,000 small molecules, including FDA-approved drugs, permitted us to recognize six drug-like molecules targeting the dimeric sites. These molecules could be promising due to their stable interactions with NS1 throughout the simulation.