Comparative docking of dual conformations in human fatty acid synthase thioesterase domain reveals potential binding cavity for virtual screening of ligands

Abstract

Human fatty acid synthase (hFASN), a homo dimeric lipogenic enzyme with seven catalytic domains, is an important clinical target in cancer, metabolic syndrome and infections. Here, molecular modelling and docking methods were implemented to examine the inter-molecular interactions of thioesterase (TE) domain in hFASN with its physiological substrate, and to identify potential chemical inhibitors. TE catalyses the hydrolysis of thioester bond between palmitate and the 4' phosphopantetheine of acyl carrier protein, releasing 16-carbon palmitate. The crystal structure of hFASN TE in two inhibitory conformations (A and B) were geometry-optimized and used for molecular docking with palmitate, orlistat (a known FASN inhibitor) and virtual screening against compounds from National Cancer Institute (NCI) database. Relatively, low binding affinity was observed during the complex formation of palmitate with A (-.164 kcal/mol) and B (-.332 kcal/mol) forms of TE, when compared with orlistat-docked TE (A form: -5.872 kcal/mol and B form: -5.484 kcal/mol), clearly indicating that the native inhibited conformation (crystal structure) was unfavourable for substrate binding. We used these orlistat dual binding modes as positive controls for prioritizing the ligands during virtual screening. From 2, 31,617 molecules in the NCI database, 916 high-scoring compounds (hit ligands) were obtained for A-form and 4582 for B-form of the TE-domain, which were then ranked according to glide docking score, XP H bond score, absorption, distribution, metabolism and excretion and binding free energy (Prime/MM-GBSA). Consequently, two top scoring ligands (NSC: 319661 and NSC: 153166) emerged as promising drug candidates that may be tested in FASN-over-expressing diseases.

Fatty acid synthase, a novel poor prognostic factor for acute lymphoblastic leukemia which can be targeted by ginger extract

“…S4 for more details). Other gingerenone family members, not only lie on the specificity channel and block the substrate binding site, but also extend to the catalytic site and form several hydrogen bonds with important residues for catalytic activity such as Ser2308 and Tyr2343 16 , through which the enzyme could be suppressed.

Figure 5 Binding modes of fenofibrate and some gingerenone family members with FASN-TE domain.

…”

“…For TE domain, chain B of the pdb file (ID: 2PX6) was used. Subsequently, the Grid box was adjusted around the catalytic triad (Ser2308, Asp2338, His2481), specificity channel and interface cavity, all of which are important for substrate binding as described by John et al 16 . For KS domain, chain A of the pdb file (ID: 3HHD) was utilized and since it was comprised of KS-MAT didomain, the KS domain was isolated by removing the sequence from Pro410 to Pro824 as described by Pappenberger et al 39 .…”

“…IC50 values of the drugs to which R-CCRF-CEM/MVCD cell subline is resistant. www.nature.com/scientificreports/ specificity channel and block the substrate binding site, but also extend to the catalytic site and form several hydrogen bonds with important residues for catalytic activity such as Ser2308 and Tyr2343 16 , through which the enzyme could be suppressed.…”

Microsecond Simulation of the Proteoglycan-like Region of Carbonic Anhydrase IX and Design of Chemical Inhibitors Targeting pH Homeostasis in Cancer Cells

“…This extensive sampling and advanced scoring will result in highly enriched hits. 85,86 Finally, the top scoring ligands were (10%) chosen as best hits and subjected to prime MM/ GBSA scoring and were in accordance to the score. 85,86 This process was repeated for the PG epitope and for all the six sampled conformations.…”

Identification of novel antilipogenic agents targeting fatty acid biosynthesis through structure‐based virtual screening

“…The development of FAS inhibitors to combat cancer has been also investigated, in particular against breast cancer, pancreatic cancer, colon cancer, ovarian cancer . Several inhibitors such as orlistat have been designed to target the TE domain using virtual screening or hybrid compounds . In 2014, a human fatty acid synthase inhibitor acting on the KR domain has been discovered and the X‐ray structure of the complex has been resolved .…”