Hello.

Well, it depends. The molecule is always shifting its conformation, influenciated by surrounding moieties. If your energy difference is about 10-15%, probably you can use one or the other. Check where the difference is (internal torsions, van der Waals, etc) because that can also give you an answer.

Thanks alot richardo you are helpful

Use all probable conformers of ligands, as the molecule of ligand should bind with target receptor in maximum conformers. Binding (in silico) may not be occuring amongst stable conformer and receptor , but orientation of molecule in the conformer which binds to target in real cellular conditions (in vivo) may not be necessarily be stable.

A few years ago, a google search revealed an article which reported that in many of the co-crystal structures in PDB, the ligand is in a "strained" conformation. Sorry I don't have the exact reference just now, but I am sure you can find it. What is "strained" and what is not actually depends on (as Ricardo pointed out) the local bioenvironment - in this case the protein residues and other moities in the vicinity of the ligand. Some computationals experiments we did (unpublished work) also revealed that the final pose and conformation of the ligand after docking was indpendent of whether or not we gave the energy-minimized (in vaccuum) conformation as starting structure. Stability is relative :-)

I do agree with the observation refered to in the answer mentioned by Chandrika B-Rao about the bio-environment resulting in binding of molecule in starined conformer. Actually, I get sometime very much surprised with the way some people, concerned with CADD, think. It is just a simple logic. Expalnation: A molecule can exist in any conformer depending on the energy prevailing in the environment it is in. At room temperature, the molecule will exist in the most stable conformer wherein the torsional stain it experiences is minimum. But, in biological system, the prevailing energy may not be guessed (predicted), so a molecule may orient itself in any conformer depending on the energy prevailing in the environment. And if the structure of the protein (receptor) has binding groups protruded towards the ligand in most strained conformer, both will bind. For better understanding, compare 1, 3-cyclohenane diol with 1, 4-cyclohaxane diol. The former is isolated in staggered conformer while the latter is isolated in the ecilipsed conformer this is the most strained but still exists due to intramoecular hydrogen bonding between two hydroxy groups thrown closer.