Apr 28 2020
Atomic Property Fields (APF) is a 3D pharmacophoric potential implemented on a grid. APF can be generated from one or multiple ligands and seven properties are assigned from empiric physico-chemical components (hydrogen bond donors, acceptors, Sp2 hybridization, lipophilicity, size, electropositive/negative and charge).Here we describe template APF superposition whereby the APF is generated from a single or multiple template and is then globally optimized with the internal force-field energy of the ligand. You can read more about the APF method here.
About this Example In this example we will use Atomic Property Fields to superimpose, screen and cluster a set of Non-nucleoside reverse-transcriptase inhibitors (NNRTIs) (antiretroviral drugs) used in the treatment of human immunodeficiency virus (HIV). We will use a non-trivial superposition example of two NNRTIs which have similar pharmacophoric properties but are significantly different substructure. We will then read in additional PDBs which contain first generation NNRTIs approved by the FDA (Nevirapine, Delavirdine, Efavirenz) we will then use the combined fields to screen an sdf library to the APF fields
NNRTIs are chemically diverse but bind in the same allosteric pocket in the palm domain of the p66 subunit and part of the p51 subunit. Many NNRTIs bind in a "butterfly" conformation (see image below of Nevirapine) making pi-pi interaction with the rings in the pocket.
This is an example of a non-trivial chemical superpostion, we will superimpose inhibitor UC781 to gw450557. A prepared ICM file containing the two inhibitors can be downloaded here ftp://ftp.molsoft.com/pub/workshop/ (1. cut and paste the address into a web browser. 2. Right click on apf_superposition_example.icb and choose "Save Link As". 3. Open the .icb in ICM File/Open).
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