We have collected some FAQs on LigBuilder v2.0 in the following section. Hope they will help you to use LigBuilder v2.0. If these FAQs still do not cover your question, please feel free to contact us at:
LigBuilder v1.0 first became available to the public in September, 1999. Since then, we have registered hundreds of users. As feedback, these users point out the bugs in the program and also make all kinds of comments and suggestion. All of these have been pushing us to go ahead.
Ten years past, we developed the new version: LigBuilder v2.0. Besides bug-fixing, major improvements include:
(1) A new design strategy "exploring mode" was introduced to extend the original growing and linking design strategy. With the exploring mode, the program will explore the drug chemical space automatically, which improving the creativity of the program significantly.
(2) We use multi seed structures to generate the initial generation rather than single seed structures. Furthermore, an ensemble growing and linking algorithm was applied to put a lot of seed into competition and combination to selecting the rational seeds.
(3) Improved the score function.
(4) Developed a post recommender to refine design results and reduce the false-positive ratio.
(5) Developed an embedded synthesis analysis module to enhance the synthesis accessibility of design results.
(6) Much more user-friendly.
The answer is "NO". Although DNA-based drug design shares the same concepts with protein-based drug design, there are two reasons preventing you from directly applying LigBuilder v2.0 to such a project: (1) New parameters are necessary for estimating the DNA-ligand interactions; (2) The binding site of a DNA (minor groove) is more open than a protein (usually a pocket), therefore the construction strategy may also need to be adjusted.
This is not so easy to interpret. However, the most likely reason is: you have set something wrong. The exploring mode is much more robust with immoderate parameters, but the growing mode and linking mode is very susceptible. You may look into these points first: Did you dock the seed into the binding pocket or keep them at the right place? Did you assign proper growing sites on the seed? Did you put enough seed structure for linking? Did you edit the building block library correctly? Did you set up the chemical rules too strict so actually no molecule can satisfy them? There is one thing we should mention here: the linking algorithm is more complicated than the growing algorithm. Linking between two separated structures will happen only when both conformation and chemistry are proper. Therefore, linking mode usually gives fewer results than growing mode does. Since the seed structures for linking may have no reasonable linkage between them can be made, because their positions or orientations are not "proper". So if this does happen, please modify your seed structure. Leave enough space between each fragment is a good idea. If the program still gives no result because of some mysterious reasons, please let us know.
Maybe you have noticed that LigBuilder v2.0 gives estimation of the binding affinities of the resultant molecules. It does so by using the SCORE v4.0 algorithm. It is inherited from the SCORE v2.0: Wang, R.; Liu, L.; Lai, L.; Tang, Y. "SCORE: A new empirical method for estimating the binding affinity of a protein-ligand complex", J.Mol.Model., 1998, 4, 379-394. If you want to estimate the binding affinity of a single ligand molecule to its receptor protein, you may use the "Score" function of BUILD.
LigBuilder v2.0 also estimates the octanol/water partition coefficients of the resultant molecules. It does so by using the XLOGP algorithm: Wang, R.; Gao, Y.; Lai, L. "Calculating partition coefficient by atom-additive method", Perspectives in Drug Design and Discovery, 2000, 19, 47-66. If you want to estimate the LogP value of a single molecule, you may download the XLOGP program from our website http://mdl.ipc.pku.edu.cn/cgi-bin/down.cgi
LigBuilder v2.0 is a multiple-purposed structure-based drug design program. It provides the abilities for binding pocket analyzing, lead discovery, lead optimization, mimic design, de novo design, molecule filter and synthesis analysis. The modularized function of LigBuilder v2.0 enhances the flexibility in its application and the program provides a high degree of automatization to design molecules by one-stop process. Besides, it is very easy to use --- the users like this so much.
However, it should be noted that drug design involves a lot of problems and it is a very complicated task. Although LigBuilder v2.0 provide automatic design procedure, we do not recommend user to apply this program as a black box. We suggest that user should fully understand the target protein and the settings of LigBuilder before starting a design task. Then, treat the program as a tool realizing your own design plan. Especially when analyzing the final results given by LigBuilder v2.0, we do believe that expertise is still very important.
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(These web pages are edited by Yaxia Yuan. Latest update: Jan., 2012)