Computational Identification of Tofacitinib as a Dual-Mechanism Candidate for FOP

Fibrodysplasia Ossificans Progressiva (FOP) presents the following complications: it causes progressive and irreversible heterotopic ossification, transforming soft tissue and muscles into bone, gradually trapping patients in a “second skeleton” that severely restricts their mobility and life expectancy. Currently, palliative treatments or highly restrictive clinical trials are being used in an attempt to slow down flare-ups; we propose a computational re-evaluation of already approved drugs to identify dual mechanisms of action. Although it is not a disease that generates large revenues in the drug market due to its ultra-rare nature (orphan disease), we wanted to explore whether superior and more accessible treatments could be identified. Therefore, we conducted a study that revealed unexpected potential in an existing drug. Using our complete GeoSol engine (GeoSol-αα) for virtual screening and hinge selectivity analysis, we discovered that, in theory, our proposed drug candidate (Tofacitinib) would not only inhibit the JAK pathway but also exhibit high affinity for the mutated ALK2 receptor. Furthermore, its pharmacokinetic profile indicates that it would not cross the blood-brain barrier, providing a vital neurological safety advantage. For all these reasons, we consider that it could function as a complete treatment on its own or, thanks to this dual mechanism, be combined at a lower dose than currently recommended with existing medications, reducing toxicity and significantly improving patients’ quality of life.