Toward a Random Background for Ligand Optimization
Тип публікації :
Препринт
Дата випуску :
13 травня 2026 р.
Автор(и) :
Xinyu Xu
Olivier Mailhot
G.J. Correy
XP Huang
João Braz
Da Shi
Karthik Srinivasan
Kara Zielinski
Yuliia Holota
Yuliia Kuziv
Christos Tsoutsouvas
Nathan Levinzon
Yagmur U. Doruk
Moira Rachman
Morgan Diolaiti
Maisie Stevens
Fangyu Liu
Katie Holland
Harald Hübner
Jing Wang
Yujin Wu
Alan Ashworth
Alexander Makriyannis
Yuqi Zhang
Yurii Moroz
Peter Gmeiner
Robert Abel
Aashish Manglik
Allan I. Basbaum
Bryan L. Roth
James S. Fraser
Brian K. Shoichet
Мова основного тексту :
Англійська
eKNUTSHIR URL :
Журнал :
bioRxiv (Cold Spring Harbor Laboratory)
Цитування :
[APA 7] Xinyu, X., Olivier, M., G.J., C., XP, H., João, B., Da, S., Karthik, S., Kara, Z., Yuliia, H., Yuliia, K., Christos, T., Nathan, L., Yagmur, U. D., Moira, R., Morgan, D., Maisie, S., Fangyu, L., Katie, H., Harald, H., Jing, W., Yujin, W., Alan, A., Alexander, M., Yuqi, Z., Yurii, M., Peter, G., Robert, A., Aashish, M., Allan, I. B., Bryan, L. R., James, S. F., & Brian, K. S. (2026). Toward a Random Background for Ligand Optimization. bioRxiv (Cold Spring Harbor Laboratory),. https://doi.org/10.64898/2026.05.10.724162
[ДСТУ] Toward a Random Background for Ligand Optimization / X. Xinyu et al. bioRxiv (Cold Spring Harbor Laboratory). 2026. DOI: 10.64898/2026.05.10.724162 (date of access: 11.09.2026).
Abstract Ligand optimization is central to drug discovery as hundreds of analogs might be designed and synthesized between an initial hit and a therapeutic candidate. The efficiency of this process is unclear, at least partly because there is no random background for optimization against which to compare. Such a random background might emerge from synthetically accessible but otherwise systematic random small substitutions across starting ligands, measuring likelihood of achieving a substantial improvement in affinity/potency or other property by any single perturbation. Recent literature and ligand-affinity/potency databases suggest that perhaps 10% of analogs with minor modifications improve upon a parent’s potency substantially (by ≥10-fold), but this number is clouded by reporting bias, intentional improvement, and inter-group reproducibility. To begin to establish a background expectation for ligand optimization, we comprehensively and systematically modified 18 lead molecules across six targets with single atom changes; 257 compounds were synthesized. Unexpectedly, 11.2% of these random small perturbation analogs improved potency by ≥10-fold over their parents. Conversely, these more potent analogs typically had worse in vitro pharmacokinetics (e.g. reduced metabolic stability, lower plasma free fraction). While it was possible to find analogs where the potency increase compensated for inferior exposure and half-life, resulting in more potent compounds in vivo, overall a frustrated landscape for ligand optimization is revealed. This study begins to establish a background expectation for ligand potency optimization and offers a simple strategy to do so. It also begins to quantify the challenges confronting the field in moving beyond in vitro potency.
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