Multiple Target Drug Design Using LigBuilder 3.

Designing drugs that directly interact with multiple targets is a promising approach for treating complicated diseases. In order to successfully bind to multiple targets of different families and achieve the desired ligand efficiency, multi-target-directed ligands (MTDLs) require a higher level of diversity and complexity. De novo design strategies for creating more diverse chemical entities with desired properties may present an improved approach for developing MTDLs. In this chapter, we describe a computational protocol for developing MTDLs using the first reported multi-target de novo program, LigBuilder 3, which combines a binding site prediction module with de novo drug design and optimization modules. As an illustration of each detailed procedure, we design dual-functional compounds of two well-characterized virus enzymes, HIV protease and reverse transcriptase (PR and RT, respectively), using fragments extracted from known inhibitors. LigBuilder 3 is accessible at http://www.pkumdl.cn/ligbuilder3/ .