Identification of various factors involved in adverse drug reactions in target proteins to develop therapeutic drugs with minimal/no side effect is very important. In this context, we have performed a comparative evolutionary rate analyses between the genes exhibiting drug side-effect(s) (SET) and genes showing no side effect (NSET) with an aim to increase the prediction accuracy of SET/NSET proteins using evolutionary rate determinants. We found that SET proteins are more conserved than the NSET proteins. The rates of evolution between SET and NSET protein primarily depend upon their non-complex (protein complex association number = 0) forming nature, phylogenetic age, multifunctionality, membrane localization and transmembrane helix content irrespective of their essentiality, total druggability (total number of drugs/target), m-RNA expression level and tissue expression breadth. We also introduced two novel terms ̶ killer druggability (number of drugs with killing side effect(s)/target), essential druggability (number of drugs targeting essential proteins/target) to explain the evolutionary rate variation between SET and NSET proteins. Interestingly, we noticed that SET proteins are younger than NSET proteins and multifunctional younger SET proteins are candidates of acquiring killing side effects. We provide evidence that higher killer druggability, multifunctionality and transmembrane helices support the conservation of SET proteins over NSET proteins in spite of their recent origin. By employing all these entities, our Support Vector Machine (SVM) model predicts human SET/NSET proteins to a high degree of accuracy (∼86%).

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