In the following study, two of the most commonly used and analyzed organic Rankine cycles (ORC), one with a basic set and another one with a regenerative heat exchanger, are investigated at different temperature levels below 450 K. The work involved implementing the continuous-molecular targeting approach to computer-aided molecular design in an optimization procedure using thermodynamic modeling software for generating the different ORC configurations. After finding the optimal operating parameters and ideal working fluid for each temperature range with a genetic algorithm, the performances of the cycles are compared. The results show that the most frequently investigated setup when the cycle is extended with a regenerative heat exchanger is not necessarily superior over the basic ORC. Under certain conditions, the simpler and more affordable design could lead to higher performance. Therefore, a thorough examination requires the investigation of both topologies. Also, groups of substances that may become fourth-generation refrigerants in the future due to zero ODP and low GWP were also examined.