BioSolveIT GmbH - ReCore

example 1: HIV Reverse Transcriptase

Are results similar to known inhibitors?

Here is CSD MSC194 with the two green bonds defining the query "exit vectors":

Here are results (yellow), overlaid with the query:

	Rank:	4	1	125
	CSD:	MOZJUG	CABVAD	XUCPUG
	PDB analog:	1eet	1s9e	1ddt
Here are closely related inhibitors (in orange) superimposed with the *ReCore* solutions:

	PDB:	1eet	1s9e	1ddt
	Note:	amide flip suggestion	meta substituted aromatics	a close match to a Trovirdine derivative

example 2: TRH (Thyrotropin Releasing Hormone)

How does ReCore deal with 3 cutting points ("exit vectors")?

A typical *ReCore* query was taken from a TRH CSD crystal (TRHTRT) and torsionally modified to satisfy Olson's [1] idea (cp. below). To obtain more rigid results, a "pharmacophore" priority was introduced: A ring atom has to lie within the sphere depicted in red.

Based on the query (please note the green arrows), *ReCore* generates several interesting and nicely aligning cyclic structures; here are the *ReCore* results (colored) with the query in grey:

	Rank:	12	5	6	7
	CSD:	HUWHEM	KIFZAA	SUMVEB	TCHXET
	Note:	saturated ring	aromatic ring	rings are good	a tri-subst'd 6-ring
And, actually, the tri-substituted 6-ring was the basis for a TRH peptide mimetic by Olson [1] (in orange):

example 3: Adenosine Deaminase

Applying ReCore to the concept of Fragment Merging

In the original paper [2], the authors state: "Simple linking would not have worked in this case, as the individually bound fragments (68 and 69) cause conformational changes in the protein upon binding that would have hindered a simple linking approach. Reengineering the original fragments preserved their binding contacts responsible for potency and produced vectors for merging." *ReCore* yields almost the same scaffold of the merged molecule as in the original publication. The compound resulted in a dramatically improved potency. *ReCore* yielded the scaffold replacement within seconds only. Using your corporate compounds as a starting point for a fragment library, your possibility of replacements would grow dramatically.

	PDB:	1ndv	2e1w

		The cutting points are defined by the exit vectors shown in green.
Here are the results:

	Rank:	5	6	12
	DUD:	ZINC03431169	ZINC00616467	ZINC00634089

[1]	Olson et al., . J. Med. Chem. 1995, 38, 2866-2879.
[2]	Erlanson, D.A. et al., . J. Med. Chem. 2004, 47, 3463 ff.

Last modified Monday, 05. Jul 2010 13:57 CEST by WebMaster