Predicting drug-target binding kinetics through multi-scale simulations

药物靶标结合动力学最近成为决定先导化合物体内有效性和毒性的一个重要参数。不幸的是，合理优化这一参数以设计更有效和毒性更低的药物是极其困难的，因为影响结合动力学的小配体及其蛋白质靶标的特征仍然知之甚少。这个项目的目的是通过结合最先进的计算方法来系统地填补这一知识空白。我们建议结合我们最先进的增强采样和QM/MM方法来计算可靠的缔合自由能分布，并根据过渡态系综的结构和能量来合理化受体-配体络合物的结合动力学。我们将测试和验证这些方法，这些方法以前没有为此目的而组合在一起。它们共同解决了生物分子模拟的两个核心挑战，即构象采样和势的准确性。我们将与制药行业合作伙伴(UCB、GSK和赛诺菲)合作，将我们开发的技术应用于具有真正生物医学重要性的具有良好特性的生物分子系统，例如流感靶标神经氨酸酶、抗癌靶标P38A、Abl、Src和FGFR酪氨酸激酶、伴侣HSP90和其他药物靶标。这一结果将为药物结合的动力学及其分子起源提供新的线索。我们开发的方法应该得到广泛的应用，我们将使它们变得可用和可用。

Drug-target binding kinetics has recently emerged as a critical parameter in determining the in vivo efficacy and toxicity of lead compounds. Unfortunately, the rational optimisation of this parameter to design more effective and less toxic drugs is extremely difficult as the features of small ligands and their protein targets that affect binding kinetics remain poorly understood. The aim of this project is to systematically fill this knowledge gap by combining state of the art computational approaches. We propose to combine our state-of-the-art enhanced sampling and QM/MM methods to compute reliable association free energy profiles and rationalise the binding kinetics of receptor-ligand complexes in terms of the structures and energies of the transition state ensemble. We will test and validate these methods, which have not been previously combined for this purpose. Together, they tackle the two central challenges of biomolecular simulation, i.e. conformational sampling and accuracy of potentials. We will apply the techniques we develop to well-characterised biomolecular systems of real biomedical importance, such as the influenza target neuraminidase, the anti-cancer targets p38a, Abl, Src and FGFr tyrosine-kinases, the chaperone HSP90, and other drug targets in collaboration with our pharmaceutical industrial partners (UCB, GSK and Sanofi). The results will shed new light on the kinetics of drug binding and their molecular origins. The methods we develop should find wide application, and we will make them available and accessible.