Drug Res (Stuttg) 2019; 69(12): 643-649
DOI: 10.1055/a-0807-8640
Original Article
© Georg Thieme Verlag KG Stuttgart · New York

Membrane-Bound Transcription Factor Site-1 Protease in PF429242 Bound State: Computational Kinetics and Dynamics of Reversible Binding

Omotuyi I. Olaposi
1   Center for Bio-Computing and Drug Development, Adekunle Ajasin University, Akungba-Akoko, Ondo State Nigeria
,
Nash Oyekanmi
2   Center for Genomics Research and Innovation, National Biotechnology Development Agency, Abuja
,
Ayodeji A. Ojo
3   Department of Public and Community Health, Liberty University, Lynchburg Virginia, United States
,
Gabriel O. Eniafe
1   Center for Bio-Computing and Drug Development, Adekunle Ajasin University, Akungba-Akoko, Ondo State Nigeria
› Author Affiliations
Further Information

Publication History

received  12 July 2018

accepted  23 November 2018

Publication Date:
14 August 2019 (online)

Abstract

Membrane-bound transcription factor site-1 protease (S1P) is an emerging clinical target due to its roles in lipogenesis, lysosomal biogenesis, unfolded protein response and viral glycoprotein processing. In this study, homology model of S1P was created in order to understand the structural basis for S1P inhibition by PF429242 using molecular docking, molecular dynamics simulation and in silico kinetics studies. PF429242 was docked (GlideScorePF429242=−5.20 kcal/mol) into the catalytic triad (D218, H249 and S414) and validated (R2=0.5686). The reversible binding kinetic parameter (Koff/Kon) was estimated at=7.28E-03 M with fully bound and apo-states interspersed by 3 transient ligand-bound states with unique binding signatures; water plays a major role in PF429242 dissociation from the catalytic site. Communication between key catalytic triad residues is altered in the presence of PF429242. In apo-S1P state, S414–S307/V216-D218 is the preferred route but in PF429242-bound state, S414-S417/V216-D218 is preferred. Communication between S414 and H249 is also shortened in PF429242 bound state; here, only L410 is required unlike apo-state, which requires P418, V256 and F252. Ligand binding did not alter the communication route between S414 and H249 as both recruited D244 and G220. In conclusion, PF429242 binds tightly but reversible to S1P and the details of this interaction has been presented to guide future efforts at developing novel inhibitors. Site-1-protease; PF429242; Kon/Koff; Network analysis

Supporting Information

 
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