Over several centuries, infectious diseases caused by viruses have been a serious threat for human health globally. Even though the numbers new highly effective antiviral drugs or vaccines have been developed for the treatment rapidly, but there are plenty of newly emerge viruses that have no proper specific treatment. In addition, the reemergence of new drug resistance viral strain is a huge challenge for drug development. This dissertation presents studies the therapeutic approach of major infectious viral diseases by proper drug target selection, design of small molecules, and test the effectiveness of small molecules experimentally. In chapter 1, we discovered inhibitors containing thiuram disulfide or dithiobis-(thioformate) tested against three key proteases in The Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) replication including Main Protease (Mpro), SARS CoV-2 Papain Like Protease (PLpro), and human cathepsin L. The use of thiuram disulfide and dithiobis-(thioformate) covalent inhibitor warheads was inspired by disulfiram, a currently prescribed drug commonly used to treat chronic alcoholism that at the present time is in Phase 2 clinical trials against SARS-CoV-2. At the maximal allowed dose, disulfiram is associated with adverse effects. We found a few compounds that were more potent than disulfiram in the enzymatic assays against SARS-CoV-2 Mpro, SARS-CoV-2 PLpro, and human cathepsin L. The identified protease inhibitors in this series were also tested against SARS CoV-2 in a cell-based and toxicity assay and were shown to have similar or greater antiviral effect than Disulfiram. In chapter 2, we identified a novel transient deep and hydrophobic pocket of the “super-open” conformation of Zika virus (ZIKV) NS2B-NS3 protease and targeted it to overcome the limitations of the orthosteric inhibitors. We applied virtual docking screening of approximately 7 million compounds against the novel allosteric site and found seven candidates. Six out of seven top candidates selected by the docking screen inhibited ZIKV NS2B-NS3 protease proteolytic activity at low micromolar concentrations, as well as suppressing viral replication. In chapter 3, we discovered the novel class of small molecules based on a tryptophan derivative scaffold identified as hepatitis C (HCV) NS3/4A protease inhibitors that are active against both wild type and mutant form of the protease. We selected the compounds that the predicted binding poses not affected by the most frequent mutations in the active site. The top compounds had a comparable inhibition profile for the common mutant HCV GT1b D168A and the wild-type enzyme. The top three inhibitors were also tested against four human serine proteases and were shown to be specific to the viral protease. The fluorescence-based cell viability assay demonstrated a sufficient therapeutic range for the top three candidates.