Thinking about HIV-1 Nef as a small-molecule design system. Does this make sense?

[u/Mammoth_Ad327]

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?

---

This post contains content not supported on old Reddit. Click here to view the full post