Influence of Drug Binding Kinetics on Pharmacodynamic Properties
identify a biochemically efficient MoA. It is the opinion of this author that the appropriate molecular descriptors to drive a knowledge-based chemistry approach are best utilised in the optimisation phase once a lead and biochemically efficient MoA for the therapeutically appropriate response have been identified.
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Potential for mechanism-based toxicity must be addressed. The magnitude of the kinetic residence time will depend on the potential for mechanism-based toxicity. No mechanism-based toxicity allows for the achievement of maximum efficacy via very slow or irreversible dissociation kinetics. Mechanism-based toxicity requires faster kinetics, mostly likely coupled to another mechanism, in order to achieve a tolerable balance between efficacy and toxicity.
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Identification and application of the appropriate molecular descriptors will decrease the number of iterations required to identify leads and thereby reduce attrition rates. Drug discovery history tells us that if enough resources and time are spent on a tractable problem it will be solved. With respect to binding kinetics I have observed that target classes will eventually evolve to medicines with slow off rates, provided that there is no mechanism-based toxicity (antihistamines, antimuscarinics and ARBs, for example) or some other mechanism that limits the toxicity (fast off rates) when there is mechanism-based toxicity (NSAIDs, NMDA receptor antagonists). This evolution was achieved through many drug discovery iterations and the corresponding attrition. Early identification of an optimal MoA and the corresponding molecular descriptors will decrease the number of iterations required to discover a medicine, thereby reducing attrition rates and cost.
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MoA identification and optimisation require diversity generation. Identification of an optimal MoA is the key to successful drug discovery. The dynamics of chemistry, biology and physiology make it almost impossible to predict a successful MoA a priori. Systems biology may provide some insight but ultimately it will require physiological assays to connect a binding interaction through its molecular descriptors to the desired therapeutic response. Despite our efforts to engineer a perfect drug, success is limited, in part because of the multiple degrees of freedom in a dynamic biological system. Lessons can be learned from how viruses generate MoA to evade a host immune system or develop resistance to an antiviral medicine. These mechanisms ultimately require the virus to generate a large diversity of gene products. The products are then
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Biochemical efficiency provides a metric to identify optimal MoA and molecular descriptors. Biochemical efficiency provides a metric to help prioritise compounds as well as allow decisions towards optimisation of metabolic properties or MoA. An optimal kinetic MoA will reduce the potential for side effects. An inefficient mechanism requires efficacy to be achieved by increasing drug concentrations, which further increases the pressure to attain optimal pharmacokinetic and drug-like properties including metabolism, solubility and absorption. Furthermore, heterogeneity in the human population will have a negative impact when an inefficient kinetic MoA is compensated by increasing drug exposures to achieve efficacy.
Conclusion
How can application of binding kinetics reduce attrition rates? The short answer is that an optimal kinetic mechanism will provide a greater therapeutic index. The challenge is to realise the potential. To reduce attrition rates, the pharma industry has applied its focus to target selection criteria using new genomic technologies and more extensive early safety and drug-like properties analysis. Target selection and drug-like properties are required, but not necessarily sufficient, components of drug action. A further requirement is the intrinsic kinetic mechanism through which the drug communicates with physiology to provide the desired therapeutic response. n
David C Swinney is Director of Virology Biochemical Pharmacology at Roche Palo Alto. He has over 20 years of broad experience and leadership in pre-clinical drug discovery, primarily in the inflammation and virology disease areas. Dr Swinney has devoted the majority of his career to the identification of tractable drug targets, effective mechanisms of drug action, promising leads and clinical candidates to treat unmet medical needs.
Some of his contributions are presented in the 50-plus publications he has co-authored. He is using this experience to co-found the non-profit Institute for Rare and Neglected Diseases Drug Discovery (IRND3). The Institute will utilise the knowledge of drug action described in this article to efficiently discover quality clinical candidates for rare and neglected diseases. Dr Swinney has a PhD in medicinal chemistry and recognised expertise in biochemistry and pharmacology.
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