Molecular docking: a powerful approach for structure-based drug discovery

Abstract

Molecular docking has become an increasingly important tool for drug discovery. In this review, we present a brief introduction of the available molecular docking methods, and their development and applications in drug discovery. The relevant basic theories, including sampling algorithms and scoring functions, are summarized. The differences in and performance of available docking software are also discussed. Flexible receptor molecular docking approaches, especially those including backbone flexibility in receptors, are a challenge for available docking methods. A recently developed Local Move Monte Carlo (LMMC) based approach is introduced as a potential solution to flexible receptor docking problems. Three application examples of molecular docking approaches for drug discovery are provided.

Figure 1

Superimposed apo- (in yellow) and holo- (in blue) crystal structures of triosephosphate isomerase. PDB code 1YPI and 2YPI, respectively [116]. The 11 residue-loop composed of binding site is the only region that has large motion upon ligand binding (in circle).

Figure 2

Local move of a lipid tail. Six subsequent torsions change while keeping the rest of the chain to remain in its original position.

Figure 3

Loop Structure of 2act (198-205) produced by the local move MC method at 5000K and followed by clustering to generate 100 representative conformations. Black stick represents the crystal loop structure, and gray wires represent the 100 representative loop conformations.

Figure 4

Flowchart of local move Monte Carlo (LMMC) loop sampling approach for protein-ligand docking. Abbreviate: MC, Monte Carlo. ESC, Exponential Coolong Scheme. LCS, Linear Cooling Scheme.