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Molecular docking has become an important common component of the drug discovery toolbox, and its relative low-cost implications and perceived simplicity of use has stimulated an everincreasing popularity within academic communities. The inherent “garbage-in-garbage-out” defect of molecular docking, however, leads a lot of researchers to dedicate countless hours to the identification of hit compounds that later prove to be inactive. Several considerations that can greatly improve the success and enrichment of true bioactive hit compounds are commonly overlooked at the initial stages of a molecular docking study. This chapter will cover several of these considerations, including protonation states, active site waters, separating actives from decoys, consensus docking and molecular mechanics generalized-Born/surface area (MM-GBSA) rescoring, and incorporation of pharmacophoric constraints, in an attempt …