Abstract
BackgroundTargets with multiple (prerequisite or allosteric) binding sites have an increasing importance in drug design. Experimental determination of atomic resolution structures of ligands weakly bound to multiple binding sites is often challenging. Blind docking has been widely used for fast mapping of the entire target surface for multiple binding sites. Reliability of blind docking is limited by approximations of hydration models, simplified handling of molecular flexibility, and imperfect search algorithms.ResultsTo overcome such limitations, the present study introduces Wrap ‘n’ Shake (WnS), an atomic resolution method that systematically “wraps” the entire target into a monolayer of ligand molecules. Functional binding sites are extracted by a rapid molecular dynamics shaker. WnS is tested on biologically important systems such as mitogen-activated protein, tyrosine-protein kinases, key players of cellular signaling, and farnesyl pyrophosphate synthase, a target of antitumor agents.
Highlights
IntroductionTargets with multiple (prerequisite or allosteric) binding sites have an increasing importance in drug design
Targets with multiple binding sites have an increasing importance in drug design
Its high speed necessitates the use of severe approximations such as (i) restriction of the search space to the surroundings of the binding site, (ii) no or inadequate explicit hydration of the ligand-target interface, (iii) partial or complete neglect of target flexibility [2,3,4,5] during ligand binding, (iv) and non-deterministic search algorithms [1, 6] based on random number generation
Summary
Targets with multiple (prerequisite or allosteric) binding sites have an increasing importance in drug design. Blind docking has been widely used for fast mapping of the entire target surface for multiple binding sites. Reliability of blind docking is limited by approximations of hydration models, simplified handling of molecular flexibility, and imperfect search algorithms. Its high speed necessitates the use of severe approximations such as (i) restriction of the search space to the surroundings of the binding site, (ii) no or inadequate explicit hydration of the ligand-target interface, (iii) partial or complete neglect of target flexibility [2,3,4,5] during ligand binding, (iv) and non-deterministic search algorithms [1, 6] based on random number generation. Eventuality of random number generation in search engines such as Monte-Carlo or genetic algorithms [1, 5, 6] is a natural barrier of the reproducibility and reliability of the results
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
