The general protocol used for the search for novel small-molecule TLRs modulators has remained the same in most of the studies conducted so far. It consists of the following steps: i) preparation of the target structure, ii) preparation of small molecules from available libraries, iii) structure-, ligand, and/or pharmacophore-based virtual screening combined with molecular docking, iv) selection of best candidates, v) experimental testing, vi) identification of potential drug candidates. Before the selection of the best candidates, more advanced computational methods are sometimes used, e.g molecular dynamics (MD) simulations, MM-PBSA, MM-GBSA binding free energy analysis, combined with receptor-ligand interaction network analysis (Figure ). By applying those advanced methods it is possible to gain better insight into the molecular basis of ligand recognition. Usually, all-atom MD simulations of the receptor-ligand complex are performed.