Yes, you really need to correct and optimize the ligands. The reason you need to do this is because the docking program you are using needs to have the ligands with the right molecular mechanics parameters and atom types or the results will be distorted, if the docking job runs at all.

I'm partial to Schrodinger Glide but these steps are common to most preliminary ligand preparation steps.

1.)If you have access to Glide (or any other docking program), you will want to bring the structures into your project from an SDF file format. In fact, just get used to importing/exporting all your ligand files as either SDF or Smiles format.

2.) Once you have imported your files, run ligprep or other ligand prep utility. In CCG MOE, I think it's called "wash". Or try Openeye Omega (openeye tends to be very generous with academic licensing). The basic idea is to generate clean 3D structures from all of your ligands.

3.) The first step is desalting. You may see that when you download your structures, you'll get the salt form. You want to strip out the counterions and be left with the parent ion.

4.)Generally, you will want to generate all of the tautomers and make sure that all of your ionizable groups are properly protonated. If you know the absolute chirality of your ligands, make sure you set that flag when you generate the 3D structure. If you don't know it, and you want to find out which enantiomer/diasteriomer docks well, generate all of them. Be warned though that if you have several chiral carbons, you will be generating a lot of structures that you will need to check later.

5.) Most lig prep programs will run a minimization step. This is a good idea because when you start with a clean ligand, you are less likely to end up with funky aromatic rings and improper torsions and stuff that will look obviously wrong to you after you've docked them. You'll have to redock but you may not immediately realize that the fault is in the lig prep step. The same goes with preparation of the receptor. If the program you're using makes you go through what looks like a long list of tedious steps for preparation of the receptor, do it, at least the first time. With practice, you'll know which steps are important and which can be ignored.

6.) After you have generated your ligands, check them with painstaking attention to detail. In particular, check the bond order of nitrogens. They're problematic in every lig prep program I have used. Some programs will protonate aromatic nitrogens, for example the N of pyridine. You need to correct this before you go forward. You may have to manually correct the bond orders of connected atoms before you proceed. Make sure the formal charges are correct as well. If the minimized structures still look "off", reminimize them.

Now, you should be ready to dock with them.

If this all seems like a pain in the ass, it is. But it's well worth it because otherwise, you'll just be docking and docking and docking and nothing will look good. The preparation steps will give you a clean set of ligands that you can reuse. And after you get the hang of it, it won't take that long. What you are looking for after docking is that your docked ligands a.) replicate the binding mode in some fashion and b.) correspond to activity data, if available. Don't ever quote the docking score as some kind of meaningful number. It's not an absolute measurement of the goodness of the fit. It is only to be used relative to the other ligands in your set. If you are starting with a complex, make sure to always include the crystal structure ligand in your ligand set and prepare it just as you would the other ligands. Don't worry that the preparation step changes this ligand from it's starting conformation. The test of your docking program will be how closely does it replicate the binding mode of this ligand (run an RMS afterward).

Good luck.

Try gromacs (make only mdrun_em) or HyperChem (Hypercube, inc.)

Currently I'm using AMBER, thanks I will try to use HyperChem. Thanks..

HyperChem have different amber forcefields....

Try gaussian too, but using only semi-empirical theory.

Hi I am in agreement with Oleh Demchuk in using Gromacs to optimizing your ligands but I add a new one suggestion, run it first in vacuum, just to check the stability of your force field on your ligand, and then in water for 1 o 2 ns it depends on em of ligand.

I think that gromacs optimization, before docking calculations, is not essential necessary.

Depends pretty much on what you want to do with it! Docking? Then I'd recommend a GAUSSIAN minimization (best: With DFT) & to take that conformation then for the runs. If you want to perform MD simulations with the ligand: Then you need to obtain a reliable topology, and that becomes messy...

Try Schrodinger Maestro for ligand optimizing

This step of gromacs it's not necessary for optimization of complex but to choose a good force field for ligand and optimization of conformation of ligand (this last one depends of size and characteristic of ligand) as well.

Is it really useful? I mean during docking process lot of conformations will be generated by varying bonds and torsion angles. Usually, genetic algorithm and fragment based methods generate randomly the starting conformation and by scoring each solution will reach a best posing. Unless, you make docking with rigid molecules (drug and protein) minimization of the drug is not meaningful from my point of view.

Am I wrong?

Maybe the easiest option is to use LigPrep from Schrodinger Suite (http://www.schrodinger.com).

@Anthony: That depends on the program you use: in some cases, the docking program will use the input ligand structure as starting point for alternations of torsion changes. So it's always better to start with a minimized structure.

thanx for precisions Steffen ;)

Ligand-Flexible Molecular Docking simulation usually leave some torsional degree of freedom, but the molecular scaffold is kept rigid, so a good starting conformation is not mandatory... the level of theory you will use to find the best geometry depends mostly on the dimension of the molecule (assuming we are talking of simple organic molecules) but I think that in any case an Hartree-Fock optimization (I suggest GAMESS-US as a free open source software) could be taken as a very good reference (using 6-31G* basis set you will have also a good reference for RESP charges calculation).

Yes, you really need to correct and optimize the ligands. The reason you need to do this is because the docking program you are using needs to have the ligands with the right molecular mechanics parameters and atom types or the results will be distorted, if the docking job runs at all.

I'm partial to Schrodinger Glide but these steps are common to most preliminary ligand preparation steps.

1.)If you have access to Glide (or any other docking program), you will want to bring the structures into your project from an SDF file format. In fact, just get used to importing/exporting all your ligand files as either SDF or Smiles format.

2.) Once you have imported your files, run ligprep or other ligand prep utility. In CCG MOE, I think it's called "wash". Or try Openeye Omega (openeye tends to be very generous with academic licensing). The basic idea is to generate clean 3D structures from all of your ligands.

3.) The first step is desalting. You may see that when you download your structures, you'll get the salt form. You want to strip out the counterions and be left with the parent ion.

4.)Generally, you will want to generate all of the tautomers and make sure that all of your ionizable groups are properly protonated. If you know the absolute chirality of your ligands, make sure you set that flag when you generate the 3D structure. If you don't know it, and you want to find out which enantiomer/diasteriomer docks well, generate all of them. Be warned though that if you have several chiral carbons, you will be generating a lot of structures that you will need to check later.

5.) Most lig prep programs will run a minimization step. This is a good idea because when you start with a clean ligand, you are less likely to end up with funky aromatic rings and improper torsions and stuff that will look obviously wrong to you after you've docked them. You'll have to redock but you may not immediately realize that the fault is in the lig prep step. The same goes with preparation of the receptor. If the program you're using makes you go through what looks like a long list of tedious steps for preparation of the receptor, do it, at least the first time. With practice, you'll know which steps are important and which can be ignored.

6.) After you have generated your ligands, check them with painstaking attention to detail. In particular, check the bond order of nitrogens. They're problematic in every lig prep program I have used. Some programs will protonate aromatic nitrogens, for example the N of pyridine. You need to correct this before you go forward. You may have to manually correct the bond orders of connected atoms before you proceed. Make sure the formal charges are correct as well. If the minimized structures still look "off", reminimize them.

Now, you should be ready to dock with them.

If this all seems like a pain in the ass, it is. But it's well worth it because otherwise, you'll just be docking and docking and docking and nothing will look good. The preparation steps will give you a clean set of ligands that you can reuse. And after you get the hang of it, it won't take that long. What you are looking for after docking is that your docked ligands a.) replicate the binding mode in some fashion and b.) correspond to activity data, if available. Don't ever quote the docking score as some kind of meaningful number. It's not an absolute measurement of the goodness of the fit. It is only to be used relative to the other ligands in your set. If you are starting with a complex, make sure to always include the crystal structure ligand in your ligand set and prepare it just as you would the other ligands. Don't worry that the preparation step changes this ligand from it's starting conformation. The test of your docking program will be how closely does it replicate the binding mode of this ligand (run an RMS afterward).

Good luck.

Generally the docking will perform the optimization of the ligand binding to the receptor, by means of the applied force field. You have to take care, however, of the conformation of the ligand (rotational positions about single bonds) because they may not (generally do not) change properly to fit the best binding mode. My suggestion is

to start with approximately good bond lengths and bond angles and setting the starting conformation manually

Yes its recommended to do ligand optimization before start docking. An easy way for ligand optimization is to use geometry optimization option in Hyperchem.

As pointed above, docking, per se, generates dozens of geometries based on the initial geometry. I don´t really see the point to optimize the ligand before running docking (it´s senseless). The only, and the most convenient topic, would be to ensure that both the protonation and the chiral center of the molecule are well defined for the starting geometry (which could be done by Ligprep module of Schrodinger software)

After that, the charge and the geometry don´t really mind, because each docking software will automatically assign their charges to the molecule, and the geometry, will be changing according to the docking pose. However, as many dockign programs assign the protonation state based on predefined chemical patterns, having previously defined the protonated moieties will avoid that.

I agree with Anthony. During the "flexible" docking process a huge number of different conformations for ligand are generated. But on the other hand when you create "prepare" a library of compound you must be carry how to address protonation states (pH dependant), possible tautomeric states, stereoisomery, etc. From my point of view preparation of ligands is very important step.

Energetics is the correct term we should be looking at. The ligand needs to be minimized.

Minimizing doesnt do much harm, and if the structure is already optimized the results of the minimization will return the parent file.

Moreover minimization (optimization) is crucial since is its not in its native form, docking will give you bad scores.

Yes I recommend to do ligand optimization before start docking. Any program for optimisation, the parametrization is very important. The kind of molecules is very important for the program.

You may check yourself whether optimization makes any difference; first docking with optimized ligand and then repeating the experiment without the optimized ligand.

I’m using ''PRODRUG" server and 'Gaussian'' for ligand optimization (Energy minimize).

Ligand Optimization Procedure:

1. Convert your ligand MOL2 to PDB format file using OpenBabel software (http://openbabel.org/wiki/Get_Open_Babel)

2. Go to PRODRUG server (http://davapc1.bioch.dundee.ac.uk/prodrg/submit.html) paste your ligand PDB file and submit.

3. Get your optimized ligand through mail link. Now your ligand ready to dock...

For docking many server(s) helpful for us. Example: Patchdock-Docking, PRODRUG-Ligand optimization, pdbsum generate, Q-sitefinder and etc.,

If you have any doubts post the comments…

Dear Dr. Mani Maran , do you think PRODRG ligand optimization is good enough than using other drawing software? I try to optimize ligand using PRODRG, which pdb file output is suitable for docking, currently I had chose the one with polar hydrogen. For docking, I've used AutoDock software.

Btw, I really want to thanks all the comment and suggestion given. It does really help me a lot. Thank you so much..

Dear Fadhilah Mazlan, ‘PRODRUG’ server gives good results* compare to the other servers. I believe his results sufficient to do Dock. You select "All Hydrogen" pdb file from the PRODRG server output files.

*Many researchers suggest me to use this server for ligand optimization.

Thank you Dr. Mani Maran for the information given. I'm really appreciate it.

thank you D. Mani Maran