Elucidating the linagliptin and fibroblast activation protein binding mechanism through molecular dynamics and binding free energy analysis

Mingsong Shi; Fang Wang; Zhou Lu; Yuan Yin; Xueting Zheng; Decai Wang; Xianfu Cai; Meng Jing; Jianjun Wang; Junxian Chen; Xile Jiang; Wenliang Yu; Xiaoan Li

doi:10.1016/j.isci.2024.111368

Elucidating the linagliptin and fibroblast activation protein binding mechanism through molecular dynamics and binding free energy analysis

iScience. 2024 Nov 13;27(12):111368. doi: 10.1016/j.isci.2024.111368. eCollection 2024 Dec 20.

Authors

Mingsong Shi^{1

2}, Fang Wang², Zhou Lu¹, Yuan Yin¹, Xueting Zheng¹, Decai Wang³, Xianfu Cai³, Meng Jing⁴, Jianjun Wang³, Junxian Chen⁵, Xile Jiang², Wenliang Yu⁶, Xiaoan Li^{1

7}

Affiliations

¹ NHC Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, Sichuan 621099, China.
² Department of Clinical Nutrition, Innovation Center of Nursing Research, Nursing Key Laboratory of Sichuan Province, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
³ Department of Hepatobiliary Surgery, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, Sichuan 621099, China.
⁴ Department of Pathology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, Sichuan 621099, China.
⁵ Key Laboratory of General Chemistry of the National Ethnic Affairs Commission, School of Chemistry and Environment, Southwest Minzu University, Chengdu 610041, Sichuan, China.
⁶ Department of Obstetrics and Gynecology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, Sichuan 621099, China.
⁷ Department of Gastroenterology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, Sichuan 621099, China.

Abstract

Fibroblast activation protein (FAP) is highly expressed in solid tumors and may be a potential diagnostic and therapeutic target in solid cancers. Linagliptin inhibits FAP; however, the interaction mechanism between linagliptin and FAP remains unclear. In this study, the binding free energy for linagliptin with human FAP was estimated at -13.66 kcal/mol, and the dissociation constant was 243 nM based on surface plasmon resonance analyses. E203, E204, and Y656 formed hydrogen bonds with ammonium. Y625 formed an unstable hydrogen bond with the carbonyl group. W623 and Y541 interacted with the quinazoline and pyrimidine-2,4-dione rings, respectively, via π-π interactions. The butyne group formed hydrophobic interactions with residues V650, Y653, Y656, and Y660. ZINC000299754517 and ZINC000299754576 were identified as potential FAP inhibitors. The R1 and R4 regions of linagliptin could be optimized to increase its FAP binding affinity. These findings can guide linagliptin structural optimization to improve its FAP binding affinity.

Keywords: Biological sciences; Chemistry; Physics.