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We describe a new library generation method, Machine-based Identification of Molecules Inside Characterized Space (MIMICS), that generates sets of molecules inspired by a text-based input. MIMICS-generated libraries were found to preserve distributions of properties while simultaneously increasing structural diversity. Newly identified MIMICS-generated compounds were found to be bioactive as inhibitors of specific components of the unfolded protein response (UPR) and the VEGFR2 pathway in cell-based assays, thus confirming the applicability of this methodology toward drug design applications. Wider application of MIMICS could facilitate the efficient utilization of chemical space.

SignificanceRadiation therapy for head and neck cancer often leads to dry mouth, a debilitating condition that affects speaking, swallowing, and other functions related to quality of life. Since salivary functional recovery after radiation is largely dependent on the number of surviving salivary stem/progenitor cells (SSPCs), we reasoned that protection of SSPCs from injury is critical for mitigating dry mouth. Following radiation, SSPCs accumulate toxic aldehydes that damage DNA, proteins, and lipids, leading to cell death. Here, we identified d-limonene as an activator of aldehyde dehydrogenase 3A1 (ALDH3A1) with a favorable safety profile for clinical use. ALDH3A1 activation decreases aldehyde accumulation in SSPCs, increases sphere-forming ability, reduces apoptosis, and preserves salivary gland structure and function following radiation without reducing the anticancer effects.

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