Docking

J. D. Madura

Overview

DockingIntroduction

Scoring Functions

Pharmacophores

Binding Site Prediction

Docking Methods

Docking Programs

Docking Protocol

Protein-Protein Docking

SummaryLearning Outcomes

DockingDocking

J. D. Madura

Department of Chemistry and BiochemistryCenter for Computational Chemistry

Duquesne University

June 18, 2015

Docking

J. D. Madura

Overview

DockingIntroduction

Scoring Functions

Pharmacophores

Binding Site Prediction

Docking Methods

Docking Programs

Docking Protocol

Protein-Protein Docking

SummaryLearning Outcomes

Overview

Consider the following figure

+ ∆G−−→ ?

Where and how does the small molecule (substrate) fitinto the protein (receptor)?

Docking

J. D. Madura

Overview

DockingIntroduction

Scoring Functions

Pharmacophores

Binding Site Prediction

Docking Methods

Docking Programs

Docking Protocol

Protein-Protein Docking

SummaryLearning Outcomes

Lecture Objectives

I Understand the principle of docking.I Become familiar with various scoring methods.I Learn about pharmacophores.I Learn how to perform free energy simulations.

Docking

J. D. Madura

Overview

DockingIntroduction

Scoring Functions

Pharmacophores

Binding Site Prediction

Docking Methods

Docking Programs

Docking Protocol

Protein-Protein Docking

SummaryLearning Outcomes

DockingDocking is the process by which two molecules fittogether in 3D space.

Different types of dockinginclude

I Receptor-substratedocking

I Protein-smallmolecule

I DNA-small moleculeI DNA-protein

I Protein-Protein docking

The goals of docking are to be (i) robust and accurateand (ii) computationally feasible.

Docking

J. D. Madura

Overview

DockingIntroduction

Scoring Functions

Pharmacophores

Binding Site Prediction

Docking Methods

Docking Programs

Docking Protocol

Protein-Protein Docking

SummaryLearning Outcomes

Receptor-Substrate Docking

I Deals with identificationof suitable (“best”)ligands for specificreceptors in proteins.

I Ligands can act eitheras activators or asinhibitors of thebiological function of theprotein in the cell.

I Artificial ligands (i.e.drugs) can be used toup-regulate ordown-regulate theactivity of proteins thatare associated withspecific diseases.

To the left, HIV-1 Proteasecomplexed with an efficientinhibitor, TL-3-093.

Docking

J. D. Madura

Overview

DockingIntroduction

Scoring Functions

Pharmacophores

Binding Site Prediction

Docking Methods

Docking Programs

Docking Protocol

Protein-Protein Docking

SummaryLearning Outcomes

Docking Considerations

Terms to consider in docking includeI Shape complementarityI Interaction specificityI Solvation/desolvationI HydrophobicI Hydrogen bondingI Substrate bound conformation (bioactive

conformation)I Protein conformation

Docking

J. D. Madura

Overview

DockingIntroduction

Scoring Functions

Pharmacophores

Binding Site Prediction

Docking Methods

Docking Programs

Docking Protocol

Protein-Protein Docking

SummaryLearning Outcomes

Scoring Functions

I Empirical

I Knowledge-based

I Physics-based

Docking

J. D. Madura

Overview

DockingIntroduction

Scoring Functions

Pharmacophores

Binding Site Prediction

Docking Methods

Docking Programs

Docking Protocol

Protein-Protein Docking

SummaryLearning Outcomes

Pharmacophore

“A pharmacophore is theensemble of steric andelectronic features that isnecessary to ensure theoptimal supramolecularinteractions with a specificbiological target structureand to trigger (or block) itsbiologicalresponse.”[Wermuth, et al.Pure Appl. Chem., 1988, 70,1129-1143.]

Docking

J. D. Madura

Overview

DockingIntroduction

Scoring Functions

Pharmacophores

Binding Site Prediction

Docking Methods

Docking Programs

Docking Protocol

Protein-Protein Docking

SummaryLearning Outcomes

Binding Site PredictionI PocketPicker. Pymol plugin for PocketPicker, a

program for the analysis of ligand binding-sites withshape descriptors.

I POVME. Free and open source program formeasuring binding-pocket volumes.

I SiteFinder in MOE. Uses alpha spheres to identifycavities that are suitable to bind substrates.

I RED - hydrophilicI WHITE - hydrophobic

Docking

J. D. Madura

Overview

DockingIntroduction

Scoring Functions

Pharmacophores

Binding Site Prediction

Docking Methods

Docking Programs

Docking Protocol

Protein-Protein Docking

SummaryLearning Outcomes

Grid-Based Docking

Grid-based docking was one of the first methods toperform docking calculations.

I Energy evaluationI Grid-based

I Search engineI Monte Carlo (MC)I Simulated Annealing

(SA)I Genetic Algorithms

(GA)

Docking

J. D. Madura

Overview

DockingIntroduction

Scoring Functions

Pharmacophores

Binding Site Prediction

Docking Methods

Docking Programs

Docking Protocol

Protein-Protein Docking

SummaryLearning Outcomes

Docking ProgramsI DOCK: Anchor-and-Grow based docking program. Flexible ligand.

Flexible protein.I Autodock: Free open source EA based docking software. Flexible ligand.

Flexible protein side chains.I MOE-Dock: Suite of medicinal chemistry tools like Ligand-Receptor

Docking, Protein/Ligand Interaction Diagrams, Contact Statistics,Electrostatic, & Interaction Maps, LigX (Ligand Optimization in Pocket),Ligand & Structure-Based Scaffold Replacement, Multiple MoleculeFlexible Alignment, Conformation Generation, Analysis, & Clustering,Active Site Detection & Visualization, Multi-Fragment Search, Ligand &Structure-Based Query Editor, High-Throughput ConformationGeneration, Pharmacophore Search.

I Gold: GA based docking program. Flexible ligand. Partial flexibility forprotein.

I FlexX: Incremental build based docking program. Flexible ligand. Proteinflexibility through ensemble of protein structure.

I Glide: Exhaustive search based docking program. Exists in extraprecision (XP), standard precision (SP) and virtual High ThroughputScreening modes. Ligand and protein flexible.

I Rosetta Ligand: Monte Carlo minimization procedure in which the rigidbody position and orientation of the small molecule and the proteinside-chain conformations are optimized simultaneously.

Docking

J. D. Madura

Overview

DockingIntroduction

Scoring Functions

Pharmacophores

Binding Site Prediction

Docking Methods

Docking Programs

Docking Protocol

Protein-Protein Docking

SummaryLearning Outcomes

Docking with MOE

Docking

J. D. Madura

Overview

DockingIntroduction

Scoring Functions

Pharmacophores

Binding Site Prediction

Docking Methods

Docking Programs

Docking Protocol

Protein-Protein Docking

SummaryLearning Outcomes

Protein-Protein DockingProtein-protein interactions play a central role in variousaspects of the structural and functional organization ofthe cell, and their elucidation is crucial for a betterunderstanding of processes such as metabolic control,signal transduction, and gene regulation.

Some protein-protein docking programsI DOT: A software package for docking macromolecules, including

proteins and DNA.I ZDOCK: Performs a full rigid-body search of docking orientations

between two proteins. The current version, 3.0.2, includes performanceoptimization and a novel pairwise statistical energy potential.

I PIPER: Performs exhaustive evaluation of an energy function indiscretized 6D space of mutual orientations of two proteins.

I HADDOCK: (High Ambiguity Driven protein-protein DOCKing) is aninformation-driven flexible docking approach for the modeling ofbiomolecular complexes.

I Hex: An interactive protein docking and molecular superpositionprogram. Hex understands protein and DNA structures in PDB format,and it can also read small-molecule SDF files.

Docking

J. D. Madura

Overview

DockingIntroduction

Scoring Functions

Pharmacophores

Binding Site Prediction

Docking Methods

Docking Programs

Docking Protocol

Protein-Protein Docking

SummaryLearning Outcomes

Learning Outcomes

You should be able toI describe the ideas behind docking.I name the three classes of scoring functions.I describe the concept of grid-based docking.I list several different docking programs.I outline the docking process.