The p53 gene is mutated in greater than 50% of several human cancers including bladder urothelial carcinoma, lung adenocarcinoma, colorectal carcinoma, and oral cancer. Mutations in the p53 gene occur predominantly in the DNA-binding domain causing loss of function and accumulation of dysfunctional p53 protein in tumors by hetero-oligomerization with the wild type p53. Thus an in silico approach for the rational design of potent, pharmacologically active small drug-like compounds targeting mutated p53 was undertaken. Molecular dynamics simulations of the wild type p53 monomer and p53 mutants R175H and R248Q were performed using Discovery Studio v3.5. Phase was used to generate pharmacophore models and the sitemap generated pocket was used to screen the Maybridge HitFinderTM library using Schrodinger Suite. We identified ten compounds (Cmpd-1 to Cmpd-10) that showed preferential binding to p53 mutants, and their pharmacokinetic profiles complied with the ADMET rules. Cmpd-4 and Cmpd-8 demonstrated binding with mutated p53 at cysteine 124, similar to the mutant p53 reactivating compound APR-246 (PRIMA-1Met) for functional restoration of the mutant p53. We propose the identified compounds as suitable drug candidates against mutated p53 protein, with the specific small drug-like molecules as either single drugs or in combination with lower doses of additional cytotoxic drugs, consequently reducing adverse side effects in patients. Communicated by Ramaswamy H. Sarma.