Introduction: Cathepsin K is being targeted for the treatment of various human disease including osteoporosis and cancer. In the present study, a compound, which contains a 2-cyanopyrimidine scaffold with optimal substituents that can interact with S2 and S3 subsites of cathepsin K, was derivatized. Objective: To determine the in silico binding affinity, the toxicity and physicochemical properties of 1-[2-(3-biphenyl)-4-methylvaleryl)] amino-3-(2pyridylsulfonyl) amino-2- propanone and its derivatives. Methods: UCSF chimera was used for macromolecule preparation and Autodock Vina was used for calculating binding affinities. PyMOL and UCSF Chimera were used to analyze the postdock binding interactions of the derivatives. Osiris property explorer was used to predict the toxicity and certain selected physicochemical properties of the derivatives. Results: The substitution of the phenoxy moiety with lipophilic substituents was found to increase the binding affinity, unlike substitutions made on the cyanopyrimidine moiety. The derivatives were found to have high binding affinity and were non-toxic, but showed low drug likeness and drug scores.