Talk:Drug design

It would be wonderful to have some examples to illustrate each of the drug design approaches mentioned in the article. The way the article reads now makes it difficult to decipher whether the methods described are in common practice or are hopeful approaches. The "Structure based" section ends with the sentence: "These techniques are raising much excitement to the drug design community" and the citation of some rather old reference material.

Is there even one example of a drug that has been developed using "structure based design" - or are there any in clinical trials?

Any one out there? —Preceding unsigned comment added by Johnfravolda (talk • contribs) 14:24, 13 August 2009 (UTC)

I agree that nebulous phrases such as "these techniques are raising much excitement to the drug design community" should be replaced with concrete examples. It appears that most of the examples listed in the "examples" section used "structure based" design methods. There are fewer examples of "ligand based" design but they do exist (some older CNS drugs come to mind). Finally it is quite common to use several different design techniques on the same project. For example, pharmacophore based database searching (i.e., virtual screening) is often used to identify hits while structure based design techniques may be used to optimize the hits. There are now many drugs currently on the market in which computer-aided drug design (CADD) techniques contributed significantly. HIV protease inhibitors and carbonic anhydrase inhibitors immediately come to mind. The application of these techniques has become so wide spread that it is probably now the exception rather than the rule when a drug makes it market without at least some contribution from CADD. I will try to add more examples when I get a chance. Boghog2 (talk) 18:46, 13 August 2009 (UTC)

Thanks for comments from Boghog2 here and above in the discussion of "discovery vs design".Johnfravolda (talk) 13:09, 14 August 2009 (UTC)

Looking at the examples provided, I would not agree that Imatinib is the product of rational design - as far as I know it comes out of a high-throughput screen as described in Deininger's and Druker's paper introducing Imatinib to the clinic^[1] and two chemical papers on Imatinib^[2][3] Would anyone be opposed to me removing this paragraph from the examples section? Momo.sander (talk) 14:59, 24 September 2013 (UTC)

From a review article co-authored by E. Buchdunger and J. Zimmermann:

Three successful examples [PKI166, PTK787/ZK222584, and STI-571 (imatinib/Gleevec)] of drug design at Novartis using a tyrosine kinase as a molecular target are described.
— Traxler, et al.^[4]

I think this is a semantic issue. Rational/drug design can be defined in a variety of ways. Rational design in the broadest sense is design knowing the target, and hence screening for tyrosine kinase inhibitors (reverse pharmacology) can be regarded as rational design. Furthermore while the initial hit leading to imatinib was obtained from screening, the structure underwent extensive optimization to improve potency, selectivity, efficacy, and bioavailability before imatinib itself was discovered.^[5] Structure based design was extensively used in this process.^[6] Clearly rational design played a major role in the discovery of imatinib.Boghog (talk) 18:52, 24 September 2013 (UTC)

I tagged the article for repetition, because structure-based drug discovery and scoring methods are described separately in separate section. The organization on the whole could be improved. Thwixly (talk) 23:59, 13 November 2013 (UTC)

The material on scoring functions is included as a subsection of structure based design hence these are not in separate sections. Furthermore scoring function ≠ structure based design. Rather scoring functions are used for structure based design. Hence I do not see this main section and it's subsection as redundant. Boghog (talk) 04:40, 14 November 2013 (UTC)

Did not mean to suggest that scoring methods and structure-based drug discovery were redundant with each other. Rather, each topic is mentioned multiple times through the article.

Redundancy 1: Scoring methods. Scoring methods are discussed in paragraph 3 of section "Rational Drug Discovery" and again in paragraph 2 of section "Computer-aided drug design". A separate set of docking scoring methods are discussed in section "Scoring Method" (section 2.2.3).

Redundancy 2: "structure-based drug design". there appears to be redundancy and overlap of scope of the whole "structure-based" section 2.2 with the "Computer-aided drug design" section, I don't see a necessary distinction between these separate sections in the overall organizational scheme. It seems to me that all structure-based drug design requires computer-aided methods (e.g., ligand-fragment linking "requires a large amount of computation"), and separating out the computer-aided methods makes the article feel redundant by the time you reach reading about it.

Redundancy 3: The introduction says "rational drug design" is another name for "drug design", yet there is a section in the article (section 3) on "rational drug discovery". Drug design is one approach to drug discovery, so the is no more-precise refinement offered by having a section on "rational drug discovery". It's like having a section titled "Blue" in the "Blue" page.

Suggested improvements: (a) I think the introduction should contain a link to the Drug Discovery page, and general discussion of drug discovery can be removed from this page (e.g., the "rational drug discovery" section), drawing some content into other sections if it must be kept. (b) A short section be added to outline what parts of the drug discovery process the drug design principles can be applied to (move the content from para. 4 of "Computer-aided drug design" to its own short section above "types" section) (c) the scoring material from the "computer-aided-design" should combined with the scoring material in "structure-based-method" (except the material for dock scoring methods), and either be put it their own "scoring methods" section or be added where appropriate to the existing structure.

I'm brand new to Wikipedia editing, so didn't want unilaterally make these improvements myself, not sure about the etiquette of that. Thwixly (talk) 12:04, 14 November 2013 (UTC)

The description of a structure based selectivity filter was added today and later removed by Jytdog, indicating that it is self promotion. The work is relevant to structure-based drug design. I don't understand why that is self promotion. — Preceding unsigned comment added by Haydee Belinky (talk • contribs) 23:54, 21 October 2014 (UTC)

every one of your edits promotes Ariel Fernandez. See WP:EXPERT Jytdog (talk) 00:47, 22 October 2014 (UTC)

Please clarify, what is your relationship to Ariel Fernandez or his lab? Thanks. Jytdog (talk) 00:49, 22 October 2014 (UTC)

We collaborate with the doctor on matters related to patent litigation. Why do you keep insisting that any quote of his work, however relevant, is promotional? The tone adopted is always neutral and the content is verifiable and relevant to the issue under consideration. We do not promote anybody. We quote Ariel Fernandez when he has done something relevant to the matter discussed, plain and simply. — Preceding unsigned comment added by Haydee Belinky (talk • contribs) 01:11, 22 October 2014 (UTC)

OK, you absolutely have a conflict of interest with regard to Ariel Fernandez. I will continue this on your Talk page. Jytdog (talk) 01:35, 22 October 2014 (UTC)

Sir, I do not have a conflict of interest with the doctor. I do not get compensated in any way by his organizations nor do I have any connection to him other than one informal exchange of opinions on a legal matter in 2011. I read the COI policy and cannot find any of what you are referring to. I quote: "The COI guideline does not absolutely prohibit people with a connection to a subject from editing articles on that subject. Editors who have such a connection can still comply with the COI guideline by discussing proposed article changes first, or by making uncontroversial edits." — Preceding unsigned comment added by Haydee Belinky (talk • contribs) 01:58, 22 October 2014 (UTC)

it is clear you have a conflict of interest. In addition, there is an WP:UNDUE issue. The "dehydron" concept does not appear to have been widely discussed or used outside Fernandez's research group (see for example Dehydron PubMed search). In addition, the dehydron concept is part of a larger phenomena that has been recognized before dehydron concept was ever formulated. Namely poorly solvated hydrogen bonding groups within binding cavities that are not necessarily restricted to backbone hydrogen bonds nor to evolutionary unconserved regions of proteins. (see for example Koehler KF, Rao SN, Snyder JP (1996). "Modeling Drug–Receptor Interactions". In Cohen NC (ed.). Guidebook on molecular modeling in drug design. San Diego, Calif.: Academic Press. ISBN 978-0121782450. The stability of the protein is sacrificed in order to create a binding site and this loss of stability may be "recaptured" by binding an appropriate ligand {{cite book}}: External link in |chapterurl= (help); Unknown parameter |chapterurl= ignored (|chapter-url= suggested) (help)CS1 maint: multiple names: authors list (link)). If this concept is included, it must be put in wider context. Boghog (talk) 06:24, 22 October 2014 (UTC)

The present article on drug design is not up to date, many of the references are of no help... But it looks some people do not want any change, I looked at the history and definitively, this is strange... So continue this way and nobody will even read it anymore... If this is the goal fine — Preceding unsigned comment added by Drugdesign94300 (talk • contribs) 21:13, 12 May 2015 (UTC)

I have been trying to add a link also very relevant to the topic, WWW.VLS3D.com and just like for the clik2drugs link, i have been removed by Jytdog. I do not understand the rational, how such an article with old and obsolete references can not be updated by experts in the field ! Interesting communication here ! If people get some insights about drug design with is here, fine with me.. no time to waste — Preceding unsigned comment added by Drugdesign94300 (talk • contribs) 21:06, 12 May 2015 (UTC)

thank you for coming to talk, finally. one thing at a time. what is your relationship with the folks who run clik2drugs? Thanks. Jytdog (talk) 03:46, 13 May 2015 (UTC)

i do not understand your statement, I am, and the people at Click2drugs, a scientist working in the field for about 30 years. Just asking with this tone gives the idea that is page is maintained by some fascist party. As you ask like if i was or they were criminals, here is the answer: I have no relation with the Click2drugs group but I know their work, like most people in the field. When you say thank for coming to talk, I could return the question, why do you delete everything without discussing with the users or people ? This is surprising to me. Are you here to tell the rest of us what to think ? what could be useful for instance for biologists who are trying to work with rational design ... The way this article is written, people do not get much help with rational design, at least from the silico tools that are available today. Of course they read that a simulation some 10 years ago was helpful, but please, it does not really help a biologist here to know this. I added the VLS3D site because in my opinion it contains a lot of in silico tools that assist drug design, it is maintain by people working in the field, it is updated as compared to many other related sites that stopped implementing tools in 2011 or 2012.., there, nothing to sell, most of the tools a free to use, at least for academic people, students, and most of the time for the private sector as well. Thus, if you ask me some rational, what is the point to give users one package, SPORCalc, in the middle of nowhere, users should get a list of tools and not one tool, and decide what is good for them. The SPORCalc, published in 2009 has been cited in 17 studies, well, why is this tool here then ? Why one tool and not a list of tools ? Many references are old and of no interest in 2015. For many sections, some major reviews, well cited reviews... should be added. As it seems that we are on a page that benefits some private interests and some people and not the community, I ll not interfere, I just stop here. I do not fit, you decide until new editors will come and hopefully optimize the page — Preceding unsigned comment added by Drugdesign94300 (talk • contribs) 06:45, 13 May 2015 (UTC)

Hi - for background, you might or might not be surprised to hear that a lot of people try to use Wikipedia to advertise their products and services; academics also try to use Wikipedia to promote their own work. Both are an abuse of Wikipedia, per the policy WP:PROMO. The behavior you demonstrated of WP:EDITWARRING rather than discussing, is typical of folks who edit with a conflict of interest. It was a simple question about clik2drugs, you answered it, and that is done. I didn't ask about VLS3D.com - are you related to the folks who run that site?

Please do keep in mind that this is an encyclopedia and is meant to describe things - not tell people how to do things nor provide them tools for doing things -- see WP:NOTHOWTO

All that said, I agree that the article very much needs updating; we love experts who come to Wikipedia and use their expertise to improve articles and who edit according to the policies and guidelines of Wikipedia - super valuable. Please do see WP:EXPERT for more about that. One of the challenges that experts face, is while they are very accomplished in their given field, when they first come to Wikipedia they don't understand the policies and guidelines governing content and sourcing in Wikipedia (which can be confusing), and can get pretty prickly when their edits fail to "stick" because their edits don't comply. I will be happy to work with you to help you learn about them. Good luck, in any case! Jytdog (talk) 12:14, 13 May 2015 (UTC)

I understand that rules are needed. I checked wikipedia introduction about what seems to be self promotion for instance for an external link, and it seems that a link that points to a web site written by authoritative experts in the field... are appropriate, if this site is not selling or related some products... I pointed to one clear paradox here in the article, like pointing the readers to SPORCalc, I have no conflict of interest with this study or reference, it is just that it points to a very specific work, this I would say it is self promotion, it does not explain anything to readers nor give them an overview of what is available etc... To me you have a major paradox here, you say that click2drug or vls3d or some other related that users could add... is conflict of interest, or people who want to advertise their work etc... but please, between a directory of resources and one specific software, if i had to choose, obviously the directory of tools make sense as it points to basically all the work done (essentially again free tools and databases) by the scientific community in one area. Then too bad, these resources are maintained by human beings, like most resources and thus points to some names, what is the problem with this ? A computer can not generate such list accurately, thus some names show up, otherwise Wikipedia should remove all the references to scientific articles but here again they point to some names, and why this name and not that one... ? Clearly, I would rather see the papers of people who have some background written down here than people eventually totally out of the field and topic... So all of this is a mess, if one follows all recommendations nothing should be written at the end and indeed, this article does not move, it is stuck and i understand that if as soon as somebody add some knowledge the data are removed, then, this is done, no point to even have an article. It is interesting that editors seem to prefer old references that have no much meaning today that contributions that bring a bit of novelty and general knowledge.. This is to me a clear conflict of interest between the editors and the users the readers. If you ask a biologist if they want to see SPORCalc or a list of tools, i am sure they want a list of tools. But again, from my side i have nothing to win. I am just running a big lab, just running in a PhD school with 200 PhD students and 400 senior scientists working in all areas of life sciences and health sciences, so if you like the article the way it is, again, no problem. I ll stop here and let other users or else try to do something, they might succeed to move things, maybe maybe not... End of the story from my side Again, I have nothing to sell, nothing to win, no promotion and my Ego is not requiring attention, I do not care, I have a permanent position, etc... My impression, although i have many things to learn about Wikipedia, is that some people play with it, you mentioned people — Preceding unsigned comment added by Drugdesign94300 (talk • contribs) 17:13, 13 May 2015 (UTC)

Yes, I agree that this article has major problems. Adding redundant, condescending, and inaccurate comments especially about lead are not helpful. Focus on improving the article. Boghog (talk) 18:54, 19 June 2015 (UTC)

ignoring ... contemporary integrative small molecule design concepts, e.g., that include physical property and ADME-Tox concerns early This is covered in the second paragraph of the lead. Boghog (talk) 18:57, 19 June 2015 (UTC)

OK, we are all on the same page - drug design is really cool and interesting, and i don't think our article does it justice..... do you think the tags are excessive now boghog? Jytdog (talk) 19:03, 19 June 2015 (UTC)

Clearly the sourcing needs to be improved. But adding tags to the entire article, to sections, and to individual citations is excessive. Boghog (talk) 19:10, 19 June 2015 (UTC)

if there are tags on sentences in sections, i agree that is too much. one or the other! Jytdog (talk) 19:23, 19 June 2015 (UTC)

Concerning PMID 7964925 which was marked as a primary source, this is a classic paper that according to Google Scholar has been cited 933 times. I have added doi:10.1021/ci500731a which is a very recent review article that cites the classic paper. I think it is appropriate that both citations are retained. Boghog (talk) 20:59, 19 June 2015 (UTC)

Concerning this edit that included the following {{Expert-subject}} rationale:

citing narrow literature more than a decade old, the lede makes narrow, academic, and contradictory statements that are editor- rather than expert- and industry opinion, initially limiting discussion to RDD, then wandering, ultimately focusing on the more traditional "ligand design" perspective, ignoring contemporary integrative drug design concepts that include physical property and ADME-Tox concerns early in the preclinical DD timeline

There are a number of problems with this statement. First and foremost, it violates a fundamental Wikipedia policy, focus on the edits, not the editors. Second, the statement is excessively long for an attention banner. The banner itself states "See the talk page for details". The |reason= parameter is "to provide a short explanation describing the issue". Third, I dispute that there was anything contradictory in the lead. The term drug design has both a narrow and a broad definition. It is important to include both definitions in the lead and there is nothing contradictory about doing so. Finally I agree that the article needs a lot more work. The errors of omission can easily be fixed and no one has claimed that this article is complete (see WP:WORKINPROGRESS). Boghog (talk) 09:19, 20 June 2015 (UTC)

Drive-by comment that the recent edits are a big improvement; nice work Boghog! Opabinia regalis (talk) 20:05, 22 June 2015 (UTC)

hi boghog in my view the specific equation presented inDrug_design#Scoring_functions is probably UNDUE for one approach and is not what we want in WP per WP:TECHNICAL.... thoughts on that? Jytdog (talk) 11:35, 21 June 2015 (UTC)

Hi Jytdog. Perhaps some of the details could be moved to Scoring functions for docking. However it should be noted that he first two equations (ΔG_bind and K_d) are basic thermodynamic expressions that are not only used within the field of compute-aided drug design but also out side it. The third is a decomposition of ΔG_bind and is also fairly generic. This was the first scoring function published and variants of it are still widely used by others. What is needed is mention of some of the other methods (e.g., empirical- and knowledge-based) for balance. I will work on this. Boghog (talk) 11:52, 21 June 2015 (UTC)

that makes sense - I hear you on the generality of the formula. Jytdog (talk) 12:44, 21 June 2015 (UTC)

After further checking, it turns out that the "master" formula that was presented was not Böhm's. I have added Böhm's formula and will try to track down the source of this "master" formula. Once I get this all sorted out, I will probably move much of the detail to Scoring functions for docking. Boghog (talk) 13:57, 22 June 2015 (UTC)

I have tracked down the source (or at least one source) of the master equation to PMID 8544170 and have updated the article accordingly. More later. Boghog (talk) 15:09, 22 June 2015 (UTC)

This article was the subject of a Wiki Education Foundation-supported course assignment, between 28 August 2023 and 15 December 2023. Further details are available on the course page. Student editor(s): Bei203 (article contribs).

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