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1432: HIV Protease Inhibitor Small Molecule Design

Closed since over 8 years ago

Intermediate Small Molecule Design Pilot

Summary

Created
September 19, 2017
Expires
Max points
100
Description

This is the first official small molecule design puzzle. The goal is to change the ligand in the center of the protein to find better inhibitors of HIV protease. Use the Ligand Design tool in the selection interface (or the "Ligand Design" mode in the original interface) to alter the chemical identity of the inhibitor. See the blog post for more information on the puzzle and small molecule design.

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Comments

Susume Lv 1

Basic chemistry time: I think I understand why each carbon has 4 atoms hanging off it (less if some are double bonds) and each oxygen has 2. But why does each nitrogen also have 4? Seems to me nitrogen should always have 3 (or 2 if there's a double bond).

Two nitrogens with 4 bonds each, an oxygen with 2, and the carbons have 4.

rmoretti Staff Lv 1

We try to model the compounds at physiological pH. (That is, at the pH one would encounter in the body.) At this pH (around pH 7 to pH 8), most amine-like nitrogens are going to be positively charged with an extra hydrogen hanging off of it, for a total of four bonds.

If you enable showing hydrogens on the protein - even on non-small molecule design puzzles - you'll notice that the sidechain amine nitrogen of lysine is also bonded to four atoms for the same reason. The backbone nitrogen is indeed only bonded to three other atoms, but it's an "amide" nitrogen, not an "amine" nitrogen, due to being right next to the carbon-double-bond-oxygen carbonyl group of the next residue segment. The ligand design code in Foldit tries to detect what sort of nitrogen is on the compound, and then put the correct number of additional hydrogens onto it, based on what would happen in a physiological pH.

Susume Lv 1

Thanks for the quick reply. I will have to google around and see if I can find some beginner-level reading that covers this.

I notice that the small molecule design lets me hang 4 heavy atoms off a nitrogen, or 3 heavy atoms with a double bond to one, or 2 carbons with double bonds to each. When I attach an oxygen to the carbon next to the nitrogen, it sometimes reduces the nitrogen's bonds to 3, but not always. At this point I am poking around randomly to see what happens; I guess foldit will get it right.

Meanwhile when I try to google "amine-like nitrogen," google thinks I want to read about "anime-like nitrogen." I guess that's a thing.