The treatment of tuberculosis (TB) usually consists of administrating series of drugs over a span of six to nine months. The important drugs prescribed to TB patients are Rifampicin and Isoniazid. The activity of rifampicin is attributed to its ability to bind and inhibit the DNA dependent RNA polymerase enzyme of bacteria. Mutations conferring rifampicin resistance (RifR) map almost exclusively to the rpoB gene that produces beta subunit of RNA polymerase enzyme. The mutation thus created produces the protein which has less binding affinity for the rifampicin thus escapes the inhibitory action of the rifampicin. Thus in the present study an insilico approach has been done to modify the structure of rifampicin structure in such a way that it can bind effectively to the mutated RNA polymerase enzyme. The three dimensional structure of RNA polymerase of M. tuberculosis and its mutants are predicted by homology modelling by MODELLER software. The predicted 3D structure was then validated with the Ramachandran plot. The derivatives of the rifampicin were prepared in ACD chemsketch software. The protein – ligand docking was performed by Hex version 8.0.0. From the present study it is evident that there is possibility of preparing rifampicin derivatives that can be sensitive for the rifampicin resistant strain of M. tuberculosis. The study also has proposed four rifampicin derivatives based on binding energy values that can be sensitive to the rifampicin resistant strain of M. tuberculosis.