The X-Score program is a simple and user-friendly program. If you experience problems in using this program, you may contact the author at the following address. We will try our best to get back to you.
Renxiao Wang, Ph.D.
Research Investigator
Department of Internal Medicine, Hematology/Oncology Division
University of Michigan Medical School
Medical Science Building I, Room 2423
1150 W. Medical Center Drive, Ann Arbor, MI 48109, U.S.A.
Tel: (734)764-2449 Fax: (734)764-2532
E-mail: renxiao@med.umich.edu
Before you contact us, please make sure you have gone through this manual and it has no answer to your question. For general questions on how to run a program on Unix/Linux platforms, please consult with a computer expert within your reach.
We are in the process of compiling a more complete FAQs for using X-Score. Any suggestion or comment on the program will be highly appreciated. We have been benefited so much by communicating with the X-Score users.
Q: Why does the program prompt me "cannot find enough pocket residues" and then stop?
A: This happens when the ligand is apart from the target protein. Please remember X-Score will NOT do docking for you. Therefore, before applying X-Score, please make sure that the ligand has been docked into the binding site of the target protein and, more importantly, they have been saved in the same coordinate system. The simplest way for checking this is to re-load the ligand and the protein on the screen to see if they indeed form the complex in the way you have desired.
Q: How to choose among the three scoring functions available in X-Score?
A: There are three empirical scoring functions implemented in X-Score, namely HPScore, HMScore, and HSScore. They only differ in the algorithm for calculating the hydrophobic effect term. Statistically, the accuracy of these scoring functions is comparable to each other, at least for the protein-ligand complex set we have used for developing X-Score. By default, all the three scoring functions are enabled and the final result is the average of three predictions. This practice is consistent with the consensus scoring strategy and is usually acceptable in most cases.
But it is also possible that, for the particular target you are studying, one particular scoring function performs better than the other two. In such situation, using that scoring function alone may lead to even more reasonable results. You may want to perform a test run first to figure out which scoring function performs better for your target.
Q. Why does X-Score use chemical rules in pre-screening?
A: It is well-known that drug-like molecules usually have a specific range of physicochemical properties. At present, this feature is typically described by some knowledge-based rules, such as the famous Lipinski's "rule of five". Our own experience in applying X-Score also suggests that by turning on the chemical rules for pre-screening, the false positives in the final results could be largely reduced. We recommend you to apply these chemical rules in structure-based virtual screening unless you have better ideas of how to select your compounds.
Q. There are some water molecules in my protein PDB file. Is X-Score able to consider them?
A: The answer is NO. X-Score will simply neglect all the water molecules. Actually all of today's scoring functions do not have a good idea for handling the water molecules existing on the protein-ligand binding interface. This is something we are working very hard on and we expect the next version of X-Score will be able to handle this.
Q. My target molecule is a DNA. Can I apply X-Score?
A: No. X-Score is an empirical scoring function which is developed for evaluating protein-ligand interactions. Its application should not be extended to DNA-ligand complexes.
Q. I noticed that X-Score requires polar hydrogens on the protein and all hydrogens for the ligand because X-Score utilizes a term for hydrogen-bonding interactions. Since hydrogen bonding is somewhat dependent on geometry, does this mean that the geometry for any groups which may be involved in hydrogen bonding must be optimized. In other words, do I need to completely optimize the hydrogen positions while keeping the heavy atoms fixed?
A: No. The coordinates of all the hydrogen atoms, on both protein and ligand, are not used at all in computation. Therefore, the positions of all hydrogen atoms do not need optimization. By the way, if you want to add all the hydrogen atoms (polar and non-polar) onto the protein, it will not hurt.
Q. Why X-Score's result is always a small number while some other scoring functions give scores around several hundred?
A: Because the scores are in different units. X-Score gives you the absolute dissociate constant of the protein-ligand complex in negative logarithm (pKd). For example, for mili-molar (mM) affinity, pKd = 3.0; for micro-molar (uM) affinity , pKd = 6.0; while for nano-molar (nM) affinity, pKd = 9.0. So usually X-Score's result is a positive number under 10.
Q. Why in the output file some of the ligands show score of zero?
A: Because you have told the program to use chemical rules to pre-screen all the ligand molecules. If any of these molecules does not meet the rules you set in the input file, it will be skipped in the later scoring process and therefore get a score of zero.
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