FBA03-TRCA-Model-CandEnzRxn-CABL-Wt-Rxn.gms is used to estimate a set of candidate enzymes and reactions. from Fuzzy optimization for identifying anti-cancer targets with few side effects in constraint-based models of head and neck cancer

Computer-aided methods can be used to screen potential candidate targets and to reduce the time and cost of drug development. In most of these methods, synthetic lethality is used as a therapeutic criterion to identify drug targets. However, these methods do not consider the side effects during the identification stage. This study developed a fuzzy multi-objective optimization for identifying anti-cancer targets that not only evaluated cancer cell mortality, but also minimized side effects due to treatment. We identified potential anti-cancer enzymes and antimetabolites for the treatment of head and neck cancer (HNC). The identified one- and two-target enzymes were primarily involved in six major pathways, namely, purine and pyrimidine metabolism and the pentose phosphate pathway. Most of the identified targets can be regulated by approved drugs; thus, these drugs are potential candidates for drug repurposing as a treatment for HNC. Furthermore, we identified antimetabolites involved in pathways similar to those identified using a gene-centric approach. Moreover, HMGCR knockdown could not block the growth of HNC cells. However, the two-target combinations of UMPS, HMGCR) and (CAD, HMGCR) could achieve cell mortality and improve metabolic deviation grades over 22% without reducing the cell viability grade.

计算机辅助方法可用于筛选潜在候选靶点，缩短药物研发周期并降低研发成本。此类方法大多以合成致死（synthetic lethality）作为治疗标准来筛选药物靶点，但此类方法在靶点筛选阶段并未考量治疗相关的副作用。本研究开发了一种用于筛选抗癌靶点的模糊多目标优化（fuzzy multi-objective optimization）方法，该方法不仅可评估癌细胞死亡率，还能最小化治疗相关副作用。本研究筛选出了可用于治疗头颈部癌（head and neck cancer, HNC）的潜在抗癌酶类与抗代谢物。本次筛选得到的单靶点与双靶点酶类主要参与六大核心通路，包括嘌呤代谢、嘧啶代谢以及磷酸戊糖途径。多数已筛选出的靶点可经获批药物调控，因此这些药物可作为头颈部癌治疗的潜在药物重定位候选方案。此外，本研究筛选出的抗代谢物所参与的通路，与采用基因中心法（gene-centric approach）得到的通路高度相似。单独敲低HMGCR无法抑制头颈部癌细胞的增殖，但UMPS与HMGCR、CAD与HMGCR这两组双靶点联合干预，可在不降低细胞活力评分的前提下，使癌细胞死亡率提升22%以上，同时改善代谢偏差评分。