Pharmacophore potential

In a related way, ensemble molecular dynamics derives a pharmacophore using restrained molecular dynamics for a collection of molecules. A force field model is set up so that none of the atoms in each molecule sees the atoms in ainy other molecule. This enables the molecules to be overlaid in space. A restraint term is included in the potential, which forces the appropriate atoms or functional groups to be overlaid in space. 

Finally, 3D pharmacophores can be used to provide a naturally partitioned space. By com bining the pharmacophore keys of a set of molecules one can determine how many of th potential 3- or 4- point pharmacophores are accessible to the set and easily identify thos which are not represented. This use of pharmacophores is the basis of a method namei Pharmacophore-Derived Queries (PDQ) [Pickett et al. 1996]. One feature of this particula method is that most molecules will occupy more than one cell (as nearly all molecules wil contain more than one 3-point pharmacophore due to the functionality present an( conformational flexibility). This contrasts with the usual situation, wherein each molecul occupies just one cell. 

In addition, researchers can survey the surface and clefts of a macromolecule for potential receptor sites based on Hgand distance ranges "use the common distance range of the superimposed atoms" (116) to faciHtate the development of a "pharmacophore" or critical contact assembly besides the Hgand... 

Fig. 10. Pharmacophores for angiotension-converting enzyme. Distances in nm. (a) The stmcture of a semirigid inhibitor and distances between essential atoms from which one pharmacophore was derived (79). (b) In another pharmacophore, atom 1 is a potential zinc ligand (sulfhydryl or carboxylate oxygen), atom 2 is a neutral hydrogen bond acceptor, atom 3 is an anion (deprotonated sulfur or charged oxygen), atom 4 indicates the direction of a hydrogen bond to atom two, and atom 5 is the central atom of a carboxylate, sulfate, or phosphate of which atom 3 is an oxygen, or atom 5 is an unsaturated carbon when atom 3 is a deprotonated sulfur. The angle 1- -2- -3- -4 is —135 to —180° or 135 to 180°, and 1- -2- -3- -5 is —90 to 90°.

Figure 13.3 Potential pharmacophore points can be generated with MOE s site detection algorithm. The white and red dots are the antomatically generated site points, and the ligand structure comes from the X-ray structure of the complex. See color plate.

The Surflex-Sim method operates significantly differently [104]. Each of the molecules is surrounded by a set of observer points that characterizes the local character of the surface and potential interactions. Two similar molecules will have a common subset of comparable observer points. A optimal alignment occurs when the differences in pharmacophore character and molecular surface inferred from the observer points are minimized between two molecules. To speed up the algorithm, large molecules can be fragmented into parts which are then compared, and then tested for consistency. This feature also makes the method capable of identifying alignments when one molecule is much smaller than the other. 

IkB kinase-p is a key regulatory enzyme in the NF-kB pathway, and inhibition of this enzyme has the potential for yielding treatments for inflammatory and autoimmune diseases. Morwick et al. [53] report on the optimization of a pM IKKp inhibitor with low aqueous solubility, moderate human liver microsome stability, and inhibition of several CYPs (3A4, 2C9, 1A2) with pM potencies. Modulation of the thiophene core (other thiophene isomer, pyrimidine and oxazole) produces compounds of similar potency to the hit. Fusing the 5-phenyl moiety to the thiophene to form a thieno[2,3-b]pyridine core increases aqueous solubility of the series as well as reduces the CYP liability. While the optimized compound still shows pM IKK(S potency, the aqueous solubility, HLM stability and CYP profiles are much improved. A pharmacophore model was generated that enabled scaffold hopping to yield this new chemotype (Scheme 7). 

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