A prospective compound screening contest identified broader inhibitors for Sirtuin 1

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Computational Biology

Background:

• Sirtuin 1 (SIRT1) is a key NAD+-dependent deacetylase implicated in various cellular processes.
• Identifying potent and diverse inhibitors of SIRT1 is crucial for therapeutic development.
• Computer-aided drug discovery (CADD) methods offer promising avenues for inhibitor identification.

Purpose of the Study:

• To identify novel inhibitors of the target enzyme, NAD-dependent deacetylase Sirtuin 1.
• To benchmark the efficacy of various in silico drug discovery approaches.
• To explore the advantage of aggregating compounds from diverse computational methods.

Main Methods:

• A contest-based approach was employed, inviting participants to propose prioritized compound lists using in silico methods.
• A large compound library of 2.5 million molecules was utilized.
• Experimental validation was performed on approximately half of the proposed compounds to assess Sirtuin 1 inhibitory activity.

Main Results:

• Seven structurally diverse compounds exhibiting inhibitory activity against Sirtuin 1 were successfully identified.
• The contest approach facilitated the aggregation of compounds with varied structural properties.
• Benchmarking of different in silico methods provided insights into their relative performance.

Conclusions:

• The contest-based approach is effective for identifying diverse potential drug candidates.
• Experimental validation is essential to confirm the efficacy of in silico-identified compounds.
• This study highlights the potential of CADD in accelerating the discovery of enzyme inhibitors like those for Sirtuin 1.