lokesh p. tripathi ncbscaps.ncbs.res.in/download/mmpli_talks/softwares_for_molecular_do… ·...
TRANSCRIPT
![Page 1: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/1.jpg)
Softwares for Molecular Docking
Lokesh P. TripathiNCBS
17 December 2007
![Page 2: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/2.jpg)
Molecular Docking
• Attempt to predict structures of an intermolecular complex between two or more molecules– Receptor-ligand (or drug)– Enzyme-substrate– Protein-DNA (or RNA)– Protein-protein
![Page 3: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/3.jpg)
Brief History of Docking
• Crick (1953) suggested that complementarity in helical coils could be modelled as knobs fitting into holes
• DOCK (Kuntz, 1982) pioneered the field of molecular docking
• GRID (Goodford, 1985) too became a part of many subsequent softwares
![Page 4: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/4.jpg)
General considerations
• Molecular representations– Abstract or atoms– Fixed or flexible
• Juxtaposition of molecules– Interactive or automated– Search algorithm to create conformations
• Evaluating complementarity (ranking)– Scoring function– Force field energy functions
![Page 5: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/5.jpg)
Search Algorithms
• Potentially several ways of putting two molecules together; possibilities increase exponentially with size of molecules involved
• Attempt to locate the most stable state in the energy landscape
• Broadly two types: 1) full solution space search; 2) guided search through solution space
![Page 6: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/6.jpg)
Search Algorithms•Random
– Genetic algorithms– Monte Carlo methods– Tabu search
•Systematic– Fragment-based methods– Point complementary methods– Distance geometry methods– Database
•Simulation– Molecular dynamics– Energy minimisation
•Multiple methods Algorithms
![Page 7: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/7.jpg)
Docking Softwares
Virtual screening De novo designAutoDock LUDI
DOCK GRIDFlexX/E MCSSSLIDE SMoG
Surflex GrowMolICM SPROUT
GOLD
![Page 8: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/8.jpg)
Random methods
• Sample the conformation space by making single change to a ligand or a population of ligands
• Alteration performed at each step and accepted or rejected based on a predetermined probability function
• Include Monte Carlo (MC) methods; Genetic Algorithm (GA) methods; Tabu search methods
![Page 9: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/9.jpg)
Monte Carlo methods• Use a simple energy function
• Makes random moves and accepting or rejecting based on Boltzmann probability function
• More efficient in stepping over energy barriers, allowing more complete searches of conformation space
• PRODOCK, MC-DOCK, ICM, DockVision, QXP, GLIDE; too slow for extensive flexible docking
![Page 10: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/10.jpg)
Energy global minimum conformers generated by Monte Carlo method
![Page 11: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/11.jpg)
Genetic Algorithm methods• Apply ideas of genetics and evolution in
docking
• Start with an initial population of random ligand conformers wrt protein, each defined by a set of variables called genes
• Genetic operators (mutations, crossovers) applied to sample conformation space till optimal population is derived
• AUTODOCK, GOLD, DIVALI, DARWIN; too slow for extensive flexible docking
![Page 12: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/12.jpg)
![Page 13: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/13.jpg)
Autodock
• Suite of automated docking tools• Designed to predict how small molecules
(ligands drug candidates) bind to a receptor; AMBER force field
• Three constituent programs-Autotors- define torsions in the ligand-Autogrid- calculate grids-Autodock- docking tool-AutoDockTools (ADT)- GUI to facilitate above and other modules accompanying AutoDock
![Page 14: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/14.jpg)
Autodock Lamarckian GA
• LGA encompasses a “genotypic” and “phenotypic” phase i.e. genetic operations and energy function to be optimised
• Energy minimisation performed after “genotypic” changes and these “phenotypic” changes mapped back onto “genes” (by changing ligand coordinates.
• Most efficient and reliable of random methods
![Page 15: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/15.jpg)
Autodock Grid maps
• Pre-calculated • Grid for each atom type
(e.g. C, H, O, N)• Consists of 3D lattice of
regularly spaced points, surrounding and centered on region of interest in the macromolecule
• Typical spacing is 0.375 Å• Probe atom placed at each
grid point and energy calculated
![Page 16: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/16.jpg)
GOLD
• Genetic Optimisation and Ligand Docking, uses multiple subpopulations of ligand
• Force-field based scoring function, includes three terms: H-bonding term, intermolecular dispersion potential, intramolecular potential
• 71% success in identifying experimental binding mode in 100 protein complexes
![Page 17: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/17.jpg)
Tabu Search methods
• Impose restrictions preventing searches from repeating already explored conformations
• New conformation is compared to the previous ones based on RMSD values which determine acceptance
• PRO-LEADS
![Page 18: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/18.jpg)
Systematic Search methods
• Attempt to explore all degrees of freedom in a molecule
• Can be divided into three types: conformational search methods, fragmentation methods, and database methods
![Page 19: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/19.jpg)
Conformational Search methods
• Brute force or shotgun methods of docking
• All rotatable bonds in ligand rotated through 360°till in fixed increments till all possible combinations generated and evaluated
• Number of structures generated increases exponentially with number of rotatable bonds- combinatorial explosion
![Page 20: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/20.jpg)
Fragmentation Search methods
• Incrementally grow ligand into the active site, by docking several fragments into the active site followed by covalent-linking to recreate the initial ligand
• Rigid core-fragment of the ligand is docked first followed by addition of flexible regions
• DOCK, FlexX, LUDI, ADAM, Hammerhead
![Page 21: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/21.jpg)
DOCK
Methodology
![Page 22: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/22.jpg)
FlexX• Base fragment is picked up and docked using
“pose-clustering” algorithm
• Clustering algorithm is implemented to merge similar ligand transformations into active site
• Flexible fragments are added incrementally using MIMUMBA and evaluated using overlap function, followed by energy calculations till the ligand is completely built
• Final evaluation through Böhm’s scoring function that includes H-bonds, ionic, aromatic and lipophilic terms
![Page 23: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/23.jpg)
Database methods• Tackle combinatorial explosion by using
libraries of pregenerated conformations to deal with ligand flexibility
• FLOG generates and docks conformational libraries called Flexibases using distance geometry
• EUDOC uses conformational searches of ligands to generate different structures, which are placed into receptor active-site followed by energy evaluation
![Page 24: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/24.jpg)
Scoring• Essential to rank the ligand conformations
determined by the search algorithms
• Scoring function must be able to distinguish between true binding modes and others
• Speed and accuracy are most desirable
• Three major classes: force-field based; empirical; knowledge-based
![Page 25: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/25.jpg)
Force-field based Scoring• Quantify sum of two energies-interaction
energy between receptor-ligand; internal energy of the ligand
• Consist of van der Waals (Lennard-Jones potential) + electrostatic energy terms (Coulombic function)
• Do not include solvation and entropic terms
• GoldScore, G-SCORE, D-SCORE, AMBER, CHARRM, GROMOS
![Page 26: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/26.jpg)
Empirical Scoring • Designed to reproduce experimental data;
binding energy can be approximated by sum of individual uncorrelated terms
• Experimentally determined binding energies used to quantify individual terms
• Easy computation, but non-versatile due to dependence on experimental datasets
• ChemScore, Böhm’s scoring function, F-Score, X-Score
![Page 27: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/27.jpg)
Knowledge-based Scoring• Statistically derived principles that aim to
replicate experimentally determined structures
• Employ simple interactions to screen large databases
• Dependent on information available in preexisting datasets
• DrugScore, SMoG score, Potential of Mean force (PMF)
![Page 28: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/28.jpg)
Consensus Scoring
• Combines information from different scoring schemes to compensate for individual limitations
• Correlation of individual scoring systems may be a problem
• X-SCORE combines functions from PMF, ChemScore, PMF with FlexX
![Page 29: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/29.jpg)
Protein-protein Docking
• Prediction of protein complex structure given individual components’ structures
• Huge number of degrees of freedom; docking largely performed as rigid body docking
• Z-DOCK, a Fast Fourier Transform-based rigid body docking program, is one of the most accurate programs as rated in Critical Assessment of Predicted Interactions (CAPRI)
![Page 30: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/30.jpg)
Docking- strengths and limitations
• Most available softwares are able to “predict” known protein-bound conformations with an accuracy of 1.5-2 Å; 70-80% success rate
• Scoring function- major limitation factor due to simplifications and assumptions
• Solvation effects, quality of crystallographic data
![Page 31: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/31.jpg)
Comparing Docking softwares in difficult
• Several studies compare docking programs but conclusions of general applicability are not evident
• Minor differences in methodology can have significant impact on success rates of various docking programs
• Cole et al., 2005 PROTEINS 60, 325-332 provide a list of recommendations in assessing docking programs
![Page 32: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/32.jpg)
Docking softwares’
representations in
citations
![Page 33: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/33.jpg)
Docking Softwares- Citations per year
![Page 34: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/34.jpg)
![Page 35: Lokesh P. Tripathi NCBScaps.ncbs.res.in/download/mmpli_talks/Softwares_for_Molecular_Do… · Attempt to predict structures of an intermolecular complex between two or more molecules](https://reader034.vdocuments.us/reader034/viewer/2022050421/5f90e47b0b8ed115325c599a/html5/thumbnails/35.jpg)
Challenges
• Predicting structures of multi-domain, multi- subunit protein complexes
• Prediction and specificity in protein-nucleic acid interactions
• Protein-docking with backbone flexibility