During my time as a Ph.D. candidate, I was tasked with creating a research proposal as part of my penultimate meeting with my doctoral committee. I was genuinely excited to take a step back from my day-to-day research and create a plan for a totally new project. Unfortunately, my advisor limited me to make proposals in his area of expertise. Fair enough, since Prof. Ojima’s area of expertise is most of medicinal chemistry anyway.
I ended up creating a proposal for discovery of novel anti-fungal agents, specifically, drugs that were bioavailable in humans since ultimately there are already a wealth of topical or agriculturally viable antifungal drugs, but not in the case of systemically useful anti-fungal drugs. Anti-fungal drugs also continue to be a hot area of research since advancing medical technologies for immunocompromised individuals are only as good as the drugs that can keep the ubiquitous fungi around us at bay. I was shocked to learn just how many fungal spores a healthy person’s immune system neutralizes on any given day. Truly magnificent.
Looking back on it now, I think there is still real potential for the project. With the discovery of next-generation fungal CYP51inhibitors, a new perspective emerged with respect to the classic method of inhibiting fungal ergosterol biosynthesis. Too many years of diminishing efficacy of fluconazole may have clouded the ultimately greater potential of a more potent CYP51 inhibitor. The fungal CYP51 inhibitor which was the basis of the molecular modelling presented in this proposal (VT-1598) is a very promising molecule with a high-resolution co-crystal structure with Aspergillus fumigatus CYP51. I used DOCK6 to score about 120,000 molecules selected for their ability to chelate the heme moiety within the enzyme. The results are interesting, with the issue of molecular synthesizability rearing its head again. Indeed, the beta-lactam compound looks quite interesting but how to efficiently synthesize a library of analogs is not clear. In any case, the work done was a great combination of computational chemistry, chemical synthesis, and biochemistry.
The actual meeting itself was one of the best days of my life. My committee, who were all quite amicable, gave me questions which lead to a genuinely interesting discussion of how to optimize the project plan. We all genuinely had a great conversation about drug discovery. I have attached the presentation here to continue the discussion about the plan with a broader audience. Email me if you’d like more details or take the project to the next step.
