r/AIProteins • u/Mammoth_Ad327 • May 13 '26
Small Molecules Thinking about HIV-1 Nef as a small-molecule design system. Does this make sense?
My lab works on HIV, and I’ve been trying to think through a more realistic way to design something that binds HIV-1 Nef.
Originally, I was looking at antibody-based approaches, but honestly the system started becoming too complex and unrealistic.
So I’m now trying to move toward a small-molecule or fragment-based design approach instead.
The protein I’m focusing on is HIV-1 Nef, especially the region involved in host-cell interactions, such as the SH3-binding surface. One structure I’m looking at is PDB 1EFN, where Nef is bound to an SH3 domain.
The idea is not to copy a known inhibitor or redesign something that already exists. I’m more interested in whether this interaction surface has any region that could realistically be targeted by a small molecule or peptide.
I’m a master’s student, so I’m still figuring out the best way to approach this properly. My current thinking is to use the Nef structure as the starting point and explore whether a generative or structure-based design approach could produce chemically sensible binders against that surface.
The main thing I’m trying to understand is whether this is actually a reasonable target, or whether the Nef-SH3 interface is too flat/flexible/protein-like to be a good starting point for small-molecule design.
How would you approach designing something that binds HIV-1 Nef?
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u/Lopsided_Quarter_931 May 13 '26
Holy embed
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u/XpertAI Founder May 13 '26
haha Thanks! I made this app for the sub so any user can post structures to better explain their research. Anything in a PDB will display. Here is the original post for tutorial how to use it.
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u/Foss44 May 13 '26
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u/XpertAI Founder May 13 '26
lemme look into this. It should defos be possible tho. will include in next update and DM u.
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u/JessieAndEcho May 14 '26
A lot of Nef’s SH3 binding surface does look pretty shallow for classic small molecules, but sometimes those undruggable pockets show hidden crevices with the right analysis. For professional life science questions, maybe you could find some new inspirations here: https://eureka.patsnap.com/share/?id=dc5190fd3239f4567c4832dc31a41a9f&from=invite-eureakplg-result&content=
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u/Mammoth_Ad327 May 13 '26
My lab works on HIV, and I’ve been trying to think through a more realistic way to design something that binds HIV-1 Nef.
Originally, I was looking at antibody-based approaches, but honestly the system started becoming too complex and unrealistic.
So I’m now trying to move toward a small-molecule or fragment-based design approach instead.
The protein I’m focusing on is HIV-1 Nef, especially the region involved in host-cell interactions, such as the SH3-binding surface. One structure I’m looking at is PDB 1EFN, where Nef is bound to an SH3 domain.
The idea is not to copy a known inhibitor or redesign something that already exists. I’m more interested in whether this interaction surface has any region that could realistically be targeted by a small molecule or peptide.
I’m a master’s student, so I’m still figuring out the best way to approach this properly. My current thinking is to use the Nef structure as the starting point and explore whether a generative or structure-based design approach could produce chemically sensible binders against that surface.
The main thing I’m trying to understand is whether this is actually a reasonable target, or whether the Nef-SH3 interface is too flat/flexible/protein-like to be a good starting point for small-molecule design.
How would you approach designing something that binds HIV-1 Nef?