School of Molecular and Cellular Biology, University of Leeds, Leeds, United Kingdom.
Vernalis (R&D) Ltd, Cambridge, United Kingdom.
Acta Crystallogr D Struct Biol. 2021 Nov 1;77(Pt 11):1348-1356. doi: 10.1107/S2059798321009712. Epub 2021 Oct 27.
The predictive power of simulation has become embedded in the infrastructure of modern economies. Computer-aided design is ubiquitous throughout industry. In aeronautical engineering, built infrastructure and materials manufacturing, simulations are routinely used to compute the performance of potential designs before construction. The ability to predict the behaviour of products is a driver of innovation by reducing the cost barrier to new designs, but also because radically novel ideas can be piloted with relatively little risk. Accurate weather forecasting is essential to guide domestic and military flight paths, and therefore the underpinning simulations are critical enough to have implications for national security. However, in the pharmaceutical and biotechnological industries, the application of computer simulations remains limited by the capabilities of the technology with respect to the complexity of molecular biology and human physiology. Over the last 30 years, molecular-modelling tools have gradually gained a degree of acceptance in the pharmaceutical industry. Drug discovery has begun to benefit from physics-based simulations. While such simulations have great potential for improved molecular design, much scepticism remains about their value. The motivations for such reservations in industry and areas where simulations show promise for efficiency gains in preclinical research are discussed. In this, the first of two complementary papers, the scientific and technical progress that needs to be made to improve the predictive power of biomolecular simulations, and how this might be achieved, is firstly discussed (Part 1). In Part 2, the status of computer simulations in pharma is contrasted with aerodynamics modelling and weather forecasting, and comments are made on the cultural changes needed for equivalent computational technologies to become integrated into life-science industries.
模拟的预测能力已经嵌入现代经济的基础设施中。计算机辅助设计在整个工业中无处不在。在航空工程、建筑基础设施和材料制造中，模拟通常用于在建造之前计算潜在设计的性能。预测产品行为的能力是创新的驱动力，它降低了新设计的成本障碍，同时也因为激进的新想法可以用相对较小的风险进行试点。准确的天气预报对于指导国内和军事飞行路径至关重要，因此作为其基础的模拟对于国家安全具有重要意义。然而，在制药和生物技术行业，计算机模拟的应用仍然受到技术相对于分子生物学和人体生理学的复杂性的限制。在过去的 30 年中，分子建模工具在制药行业逐渐获得了一定程度的认可。基于物理的模拟开始为药物发现带来益处。虽然这些模拟在改进分子设计方面具有巨大的潜力，但人们对它们的价值仍持怀疑态度。本文讨论了行业中持这种保留态度的原因以及模拟在临床前研究中提高效率方面显示出前景的领域。在这两篇互补论文的第一部分中，首先讨论了需要取得的科学和技术进展，以提高生物分子模拟的预测能力，以及如何实现这一目标（第 1 部分）。在第 2 部分中，对比了计算机模拟在制药领域的现状与空气动力学建模和天气预报，并对需要进行的文化变革发表了评论，这些变革对于将等效的计算技术集成到生命科学行业中是必要的。
