“Polypharmacology” or “multi-target pharmacology” refers to drugs that modulate the activity of multiple targets at clinically relevant concentrations. The effect of polypharmacology on therapy can be favorable, contributing to drug efficacy, reducing drug resistance, and reducing toxicity and other liabilities. Polypharmacology can be effective in a broad palette of diseases including central nervous system (CNS) disorders, diabetes, and cancer (Keiser et al., 2009). Its strength lies in the ability to “shift networks” into configurations that reduce disease while minimizing whole body toxicity. For example, a drug can hit one target to reduce disease while hitting another target to reduce the liabilities of the first target. Indeed, many—perhaps most—clinically successful drugs act through multiple targets. Nevertheless, polypharmacology is not readily embraced by pharmaceutical companies, in part due to practical challenges including (1) the difficulty in defining a useful set of multiple in vivo targets, and (2) the difficulty in developing a practical polypharmacology optimization chemistry strategy. Given the proven ability of polypharmacology to handle complex diseases, an intentional approach—“rational polypharmacology”—would be ideal (Dar et al., 2012). Rational polypharmacology represents an emerging paradigm different from that used in traditional drug discovery, in which a highly potent and selective drug is optimized to act on a single specific biological target. Given the low success rate of lead compounds in cancer clinical trials, the potential of polypharmacology has seen renewed interest. However, the practical challenges remain.

中文翻译：

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多目标毒品社区挑战

“多药理学”或“多靶标药理学”是指在临床相关浓度下调节多个靶标活性的药物。多元药理学对治疗的影响可能是有利的，有助于提高药效，降低耐药性，减少毒性和其他负担。多种药理学可以有效治疗多种疾病，包括中枢神经系统（CNS）疾病，糖尿病和癌症（Keiser等，2009）。它的优势在于能够将网络“转变”为可减少疾病并最大程度降低全身毒性的结构。例如，一种药物可以击中一个目标以减少疾病，而击中另一个目标以减少第一个目标的负担。确实，许多（也许是大多数）临床上成功的药物通过多个目标起作用。尽管如此，制药公司不容易接受多药理学，部分是由于实际挑战，包括（1）难以定义一组有用的多种体内靶标，以及（2）制定切实可行的多药理学优化化学策略的困难。鉴于多元药理学具有处理复杂疾病的成熟能力，一种有针对性的方法（“理性多元药理学”）将是理想的（Dar等人，2012）。理性多元药理学代表了一种不同于传统药物发现中的新兴范式，在传统药物发现中，高效和选择性药物被优化以作用于单个特定的生物靶标。鉴于前导化合物在癌症临床试验中的成功率较低，因此多药理学的潜力引起了人们的新兴趣。但是，实际挑战仍然存在。