Hi Johnson, I agree with Krishnendu that one really needs to understand the specifics of your system to answer correctly. However, I do not agree that docking and dynamics will necessarily give you a biologically relevant answer. Hopefully, you have good pharmacology data to help guide your modeling experiments. Drop a message with more project details/goals and I’ll get back to you with additional thoughts.

You neet to find out the binding energies in all possible combinations and then compare that. If the drug1-drug2 binding energy is less negative than the drug1-protein or drug2-protein binding energy, then in presence of protein drug1-drug2 complex will break down and the lowest energy complex will form.

Hi

It‘s difficult to comment without prior knowledge of your project, at least the protein and ligand. Anyway I’m assuming you are doing everything correct and you really need to bind two ligands in same binding pocket of protein. Then try all the combinations suggested by Uttam. After docking run md simulations and compare the results with apo-protein simulation. If binding pocket is different then dock the ligands in respective binding pockets and do MD simulation and compare the results.

Thanks a lot Uttam Pal for the informtion. i'll try different combinations to understand the minimal energy levels, and will decide on the best complex.

Also, thanks a lot Krishnendu Bera for your answer as well. That was a great piece of suggestion; And the point, where you mentioned about comparing the results to the results of apo-protein simulation was a major takeaway i got from your answer, that i was not familiar with.

Again, thanks for having your answers here.

Hi Johnson, I agree with Krishnendu that one really needs to understand the specifics of your system to answer correctly. However, I do not agree that docking and dynamics will necessarily give you a biologically relevant answer. Hopefully, you have good pharmacology data to help guide your modeling experiments. Drop a message with more project details/goals and I’ll get back to you with additional thoughts.

That's an interesting question, Johnson. I don't think I have ever come across this particular case. So, if i have your situation right, you have two drugs, both of which occupy different parts of a target pocket. You want to find out if the two drugs can bind acceptably together or even if they have synergistic binding

Firstly, i would try docking one in, and take a number of reasonable ligand-protein structures from that docking (or just one, if you are confident it is best) . Then try docking the second drug to these structures to see if it can bind in the desired way. Then do the whole process the other way round, docking the second drug first.

This might work. If it doesn't give you a nice double binding pose but you can get the two drugs binding fairly close together, then you could take that doubly bound ligand protein system and subject it to simulated annealing molecular dynamics to see if you can get a better low energy double binding pose. Alternatively, you might see one of your ligands flying away, demonstrating double binding is not possible.

One situation I can think of where this is relevant is allosteric modulators of GPCRs. Thus there is an endogenous ligand e.g. dopamine, serotonin, the the activity of the endogenous ligand is potentiated by an allosteric ligand binding in e.g. the vestibule site. In this case, dock to the vestibule site, then do careful experiments to discover any synergistic effects of the PAM or NAM on the activity of the endogenous ligand.

This reduces to one molecule docking to one site, this time the vestibule (or other allosteric) site. The end. You are not docking dopamine or serotonin at the same time.

If you have an example where two drugs bind to the same protein at the same time, please supply these examples. In general, docking is to one site at a time. Careful experimentation can reveal whether there is any potentiation of the activity of one by the other.

Hello James H Nettles , thanks a lot for your answer. I'll definitely get back with the project details. Thanks for your help & support.

And a big thanks to John J Irwin too. That was a clear elaboration on how to consider allosteric binding also into consideration.

Again, thanks for having your answers here.

I think Johnson Samuel is interested in drug dimers. Many small molecules forms dimers or multimeric aggregates. If such dimers (may be homo- or heterodimers) can interact with a target protein that is what he wants to find out using docking. But docking programs conventionally do not allow flexible docking of two non-covalent entities. One way around is to define dummy bonds to freeze the core. However, before going to that, dimerization energies should be studied and compared with the protein binding energies of the monomers.

Hello John Liebeschuetz . Your explanation gives me great insights on multi-ligand docking. But that is not exactly what i want; because, my approach here is much more fundamental. I just want to check the binding of a Drug 1-Drug 2 complex, or in other words, the heterodimers formed by those 2 Drug molecules, onto the protein, which is exactly what Uttam Pal has stated here.

Thanks Uttam Pal for that suggestion. I totally get your point there. But can i be sure that inducing dummy bonds between the 2 drugs to freeze the core, can give a conformation similar to what i'd expected, post docking? I mean is it as good as having the drug heterodimer docked to the protein?

Assuming the dimer is very stable, there should be some rigid regions where you can define dummy bond(s) to treat it as one molecule. However, creating a single molecule approximation from the dimer totally depends on the structure of the dimer. Post-docking, I would suggest MD simulation without the dummy bonds.

Johnson Samuel how big is your active site? Are ligands competetive? If yes, you should:

1. Dock ligands in different positions and compare Gibbs free energy (MM-GBSA, deltaG).

2. Start short MD calculations for every (!) position you created, calculate RMSD of the ligands and check the energy as well.

3. Select the lowest one and dock the next ligand.

4. Repeat step 2.

5. Select complexes with the lowest energies and impose them.

6. The may be not only one answer for your docking.

7. Repeat all of the steps switching the order of the selected ligands for docking.

Alright Uttam Pal . I got your point. Thanks a lot for your suggestion.

Thanks to Michał Talma as well, for those steps. Infact, the ligands ain't competitive. And instead, I want to dock both the ligands with each other, and then dock that dimer complex with the protein. This was my question.

Docking the complex which is not connected by covalent bonds is almost impossible for now, especially if you want to compare it with biological activity.

What is the mechanism then?

Have you tried multiple ligand simultaneous docking?

Article Multiple Ligand Simultaneous Docking: Orchestrated Dancing o...

Article Multiple ligand simultaneous docking (MLSD): A novel approac...

Yes Michał Talma i totally agree with you. Thats the reason, Uttam Pal had previously mentioned, that, creating dummy bonds between them (at rigid regions), provided that the complex is stable. So maybe that might help in having a good complex formation.

Multiple ligand simultaneous docking, is more or less, what i had actually been searching for. Thanks a lot Ricardo J Ferreira for sharing papers on them.

Hai Johnson Samuel, I felt many critical and knowledgeful ideas were discussed by various experts in the field. I feel John J Irwin and articles referred by Ricardo J Ferriera will be very helpful to proceed your research. For combinatorial effect first dock the ligand of interest in appropriate site (if known) in the protein. Now you have a complex structure, try to dock the second molecule in same site if you need to find the competitive binding. If not, dock the second molecule in other potential sites and evaluate its binding affinity or energy. Or else try the X-ray crystal structure with any of your ligand of interest. Refer the article Article Multiple ligand simultaneous docking (MLSD): A novel approac...

I get your point Lakshmanan Loganathan

thanks a lot for adding your suggestion here.!

See this link

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274917/

See this link

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274917/

http://journal.umpalangkaraya.ac.id/index.php/jmd/announcement/view/17

https://docs.google.com/forms/d/e/1FAIpQLSfNpiah9wUc--jA7V1_42J2M3Cjlgtvgj-vDEasBIPXbEs9MQ/viewform?usp=pp_url

Dear Colleagues,

Department of Pharmacy, Universitas Muhammadiyah Palangkaraya openly inviting researchers with expertise in the field of Molecular Docking to join the new journal that will be released in early 2021, both as an editorial board and as peer-reviewers.

We will call this journal "Journal of Molecular Docking" or "J. Mol. Docking", with a very specific aim and scope, namely various research in the field of science and health using Molecular Docking as its main method.

Currently we are still preparing the journaling platform with OJS 3.1.1.2 and will start collecting articles as soon as the editorial board and peer-reviewer members are gathered.

It should be noted that this position is voluntary, so all editors and reviewers will not receive any rewards in the form of funds. However, we will provide a certificate of appreciation for each manuscript handled, both as an editor and reviewer.

The target of this new journal is to be indexable by DOAJ after the first year and indexed by Scopus and/or ESCI WoS after the fifth year.

For this reason, we expect the willingness and participation of Molecular Docking researchers to be directly involved in the development of this new journal so that later it can become a publication benchmark for research with the molecular docking method.

Once again, we are grateful for the participation of all researchers and hope for their support to be able to create and grow this new journal.

Best regards,

Mohammad Rizki Fadhil Pratama

Department of Pharmacy

Universitas Muhammadiyah Palangkaraya

http://orcid.org/0000-0002-0727-4392

Dear sir,

I hope these articles will help you:

https://www.nature.com/articles/srep36969

Article Prediction of drug-target interactions from multi-molecular ...

Article Molecular Docking: Shifting Paradigms in Drug Discovery

Best regards