Challenges and advances in computational docking: 2009 in review

Abstract

Docking is a computational technique that places a small molecule (ligand) in the binding site of its macromolecular target (receptor) and estimates its binding affinity. This review addresses methodological developments that have occurred in the docking field in 2009, with a particular focus on the more difficult, and sometimes controversial, aspects of this promising computational discipline. These developments aim to address the main challenges of docking: receptor representation (such aspects as structural waters, side chain protonation, and, most of all, flexibility (from side chain rotation to domain movement)), ligand representation (protonation, tautomerism and stereoisomerism, and the effect of input conformation), as well as accounting for solvation and entropy of binding. This review is strongly focused on docking advances in the context of drug design, specifically in virtual screening and fragment-based drug design.

Molecular Docking and Structure-Based Drug Design Strategies

“…Molecular docking programs perform these tasks through a cyclical process, in which the ligand conformation is evaluated by specific scoring functions. This process is carried out recursively until converging to a solution of minimum energy [23][24][25].…”

“…Conformational search algorithms perform this task by applying systematic and stochastic search methods [25,26].…”

Study of the interaction of Huperzia saururus Lycopodium alkaloids with the acetylcholinesterase enzyme

“…[52,53] This has been ascribed to the different scoring functions used, issue that has been previously addressed. [9,75,76] Despite the differences in absolute binding energies, it is important to point out that the top poses obtained for each site were similar for the three docking procedures employed. The results were normalized by rescoring the binding energy of each of the final geometries.…”

Recent Advances and Future Trend on the Emerging Role of GPUs as Platforms for Virtual Screening-Based Drug Discovery

“…Docking methods have been traditionally applied to ligand database screening (Yuriev et al, 2011), where a large ligand database is screened against a single receptor molecule in order to predict potential leads. The inverse approach, the one we are interested in, where a large database of target receptors is screened against a single ligand, has not received such attention and only some attempts are reported (Hui-fang et al, 2010).…”

“…The inverse approach, the one we are interested in, where a large database of target receptors is screened against a single ligand, has not received such attention and only some attempts are reported (Hui-fang et al, 2010). In both application scenarios, most docking programs represent the receptor as a rigid molecule (Yuriev et al, 2011) thus limiting the range of applicability of their predictions. There are few reported cases where receptor flexibility has been successfully used in docking simulations (Kokh et al, 2011), but it is clear its relevance and importance for multi target drug screening.…”