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. 2007 Nov-Dec;47(6):2416-28.
doi: 10.1021/ci700271z. Epub 2007 Oct 20.

Search for non-nucleoside inhibitors of HIV-1 reverse transcriptase using chemical similarity, molecular docking, and MM-GB/SA scoring

Gabriela Barreiro  1 , Cristiano R W Guimarães, Ivan Tubert-Brohman, Theresa M Lyons, Julian Tirado-Rives, William L Jorgensen
Affiliations

Search for non-nucleoside inhibitors of HIV-1 reverse transcriptase using chemical similarity, molecular docking, and MM-GB/SA scoring

Gabriela Barreiro et al. J Chem Inf Model. 2007 Nov-Dec.

Abstract

A virtual screening protocol has been applied to seek non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) and its K103N mutant. First, a chemical similarity search on the Maybridge library was performed using known NNRTIs as reference structures. The top-ranked molecules obtained from this procedure plus 26 known NNRTIs were then docked into the binding sites of the wild-type reverse transcriptase (HIV-RT) and its K103N variant (K103N-RT) using Glide 3.5. The top-ranked 100 compounds from the docking for both proteins were post-scored with a procedure using molecular mechanics and continuum solvation (MM-GB/SA). The validity of the virtual screening protocol was supported by (i) testing of the MM-GB/SA procedure, (ii) agreement between predicted and crystallographic binding poses, (iii) recovery of known potent NNRTIs at the top of both rankings, and (iv) identification of top-scoring library compounds that are close in structure to recently reported NNRTI HTS hits. However, purchase and assaying of selected top-scoring compounds from the library failed to yield active anti-HIV agents. Nevertheless, the highest-ranked database compound, S10087, was pursued as containing a potentially viable core. Subsequent synthesis and assaying of S10087 analogues proposed by further computational analysis yielded anti-HIV agents with EC50 values as low as 310 nM. Thus, with the aid of computational tools, it was possible to evolve a false positive into a true active.

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Figures

Figure 1
Figure 1
The 26 known non-nucleoside HIV-RT inhibitors used in the virtual screening.
Figure 2
Figure 2
Comparison between the docked (light gray) and the observed crystal structures for six NNRTIs. The RMSd values are noted. All NNRTIs were docked into the 1rt4 structure.
Figure 3
Figure 3
Docking poses for three additional known NNRTIs, TMC-125, S-DABO-3w, and DPC-083.
Figure 4
Figure 4
MM-GB/SA Score (left) and Glide XP function (right) versus pIC50 for 11 NNRTIs.
Figure 5
Figure 5
ΔΔGbind versus XP docking score. S-DABO-3w, the ligand with the most favorable binding energy (ΔGbind), was used as reference to obtain ΔΔGbind.
Figure 6
Figure 6
Top 20 compounds from the MM-GB/SA post-scoring after docking into wild-type HIV-RT.
Figure 7
Figure 7
Energy-minimized complexes between HIV-RT and S10087, NRB03328, and KM06633.
Figure 8
Figure 8
(a) Overlay of the energy-minimized complexes for the best scoring 2-pyrimidines (23p (yellow), 23h (green), and 23o (magenta)). (b) Hydrophobic interactions between the arene pocket (CPK) and unsaturated groups; 3,3-dimethylallyloxy in UC-781 (dark green), methyl-pyridinyl in nevirapine (blue), benzyl in MKC-442 (magenta), 3,3-dimethylallyl in 9-Cl TIBO (light green), ethynylcyclopropyl in Sustiva (yellow), and phenoxy in TMC-125 (light blue).
Figure 9
Figure 9
Top 20 compounds ranked by the MM-GB/SA post-scoring after docking into the K103N variant of HIV-RT.
Figure 10
Figure 10
Energy-minimized complexes between K103N-RT and S-DABO-3w, DPC-963, 23o, and KM06633. All four ranked among the best 20 compounds for both HIV-RT and K103N-RT.
Figure 11
Figure 11
Modifications of S10087 that generated the anti-HIV agent JL0203.
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