In silico methods like molecular docking and pharmacophore modeling are established strategies in lead identification. Their successful application for finding new active molecules for a target is reported by a plethora of studies. However, once a potential lead is identified, lead optimization, with the focus on improving potency, selectivity, or pharmacokinetic parameters of a parent compound, is a much more complex task. Even though in silico molecular modeling methods could contribute a lot of time and cost-saving by rationally filtering synthetic optimization options, they are employed less widely in this stage of research. In this review, we highlight studies that have successfully used computer-aided SAR analysis in lead optimization and want to showcase sound methodology and easily accessible in silico tools for this purpose.

Institute of Biotechnology of the Czech Academy of Sciences BIOCEV Vestec Czech Republic

Institute of Pharmacy Department of Pharmaceutical and Medicinal Chemistry Paracelsus Medical University Salzburg Strubergasse 21 5020 Salzburg Austria

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Combination of In Silico and In Vitro Screening to Identify Novel Glutamate Carboxypeptidase II Inhibitors