PI3K/mTOR Dual Inhibitor Pictilisib Stably Binds to Site I of Human Serum Albumin as Observed by Computer Simulation, Multispectroscopic, and Microscopic Studies

Abstract

Pictilisib (GDC-0941) is a well-known dual inhibitor of class I PI3K and mTOR and is presently undergoing phase 2 clinical trials for cancer treatment. The present work investigated the dynamic behaviors and interaction mechanism between GDC-0941 and human serum albumin (HSA). Molecular docking and MD trajectory analyses revealed that GDC-0941 bound to HSA and that the binding site was positioned in subdomain IIA at Sudlow’s site I of HSA. The fluorescence intensity of HSA was strongly quenched by GDC-0941, and results showed that the HSA–GDC-0941 interaction was a static process caused by ground-state complex formation. The association constant of the HSA–GDC-0941 complex was approximately 105 M−1, reflecting moderate affinity. Thermodynamic analysis conclusions were identical with MD simulation results, which revealed that van der Waals interactions were the vital forces involved in the binding process. CD, synchronous, and 3D fluorescence spectroscopic results revealed that GDC-0941 induced the structural change in HSA. Moreover, the conformational change of HSA affected its molecular sizes, as evidenced by AFM. This work provides a useful research strategy for exploring the interaction of GDC-0941 with HSA, thus helping in the understanding of the transport and delivery of dual inhibitors in the blood circulation system.

Mechanism understanding of PIKfyve inhibitor YM201636 with human serum albumin: Insights from molecular modeling and multiple spectroscopic techniques

“…The widths of excitation and emission slits were set to 3 and 5 nm. Then, to exclude the inner‐filter effect, the observed fluorescence intensities were corrected by the following formula [18, 20]: $$$$ {F}_{corr}={F}_{obs}{e}^{\left({A}_{ex}+{A}_{em}\right)/2} $$$$ …”

“…Each sample was excited at 280 nm and the decay measurements were made at 340 nm. The spectral data were analyzed by the tail‐fitting method and the values of the average lifetime τ avg were calculated using the following equation [14, 18]: $$$$ {\tau}_{\mathrm{avg}}={\tau}_1{\alpha}_1+{\tau}_2{\alpha}_2+{\tau}_3{\alpha}_3 $$$$ where α i and τ i represent the relative contribution to total decay and the lifetime of different components, respectively.…”

“…The widths of excitation and emission slits were set to 3 and 5 nm. Then, to exclude the inner-filter effect, the observed fluorescence intensities were corrected by the following formula [18,20]:…”

“…Each sample was excited at 280 nm and the decay measurements were made at 340 nm. The spectral data were analyzed by the tail-fitting method and the values of the average lifetime τ avg were calculated using the following equation [14,18]:…”

Design, synthesis and biological evaluation of novel morpholinopyrimidine-5-carbonitrile derivatives as dual PI3K/mTOR inhibitors

“…Moreover, they entered clinical trials as PI-103, which is a powerful dual inhibitor of pan-PI3K class I isoforms and mTOR, 7,26 Apitolisib (GDC-0980) underwent phase II clinical trials for the treatment of various malignancies, which acts as a PI3K and mTOR inhibitor, 7,11,26 Bupralisib (BKM-120) underwent phase III clinical trials as a breast anticancer agent 7,26 and Pictilisb (GDC-0941) is a well-known dual inhibitor of class I PI3K. It is undergoing phase II clinical trials for cancer treatment 11,26,29,31 (Fig. 2).…”