Docking studies on short and ultra-short peptides against beta-secretase (BACE1) enzyme

Transcription

1 Research Article Docking studies on short and ultra-short peptides against beta-secretase (BACE1) enzyme Pandurangan Perumal 1, Liew Chun Lap 1, Ling Yu Luong 1, Tan Ling Hoi 1, Pavadai Parasuraman 2 ABSTRACT Objective: The objective of this study was to evaluate the short and ultra-short peptides by in silico studies against betasecretase enzyme. Method: Schrodinger, LLC. Results: The compound HH1 was found to be highly potent score of and DP IV, AIA II, and DP I were found to be potent docking score of 9.305, 8.645, and against beta-secretase (BACE1) enzyme. However, these compounds are shown to be highly effective than control AChE inhibitor donepezil ( 5.84). Conclusion: In silico docking study was done for the designed dipeptides, hexapeptides, and octapeptides against BACE1 enzyme shows highly potent binding affinity toward HH1 and DP IV peptides as compared with standard donepezil. KEY WORDS: Alzheimer s disease, Beta-secretase, Donepezil, In silico, Peptides INTRODUCTION Dementia is a clinical disorder that involves falling of intellectual function leads to various cognitive abilities can be impaired with dementia including memory, decision-making, attention, etc. The two types of dementia, one is reversible and another one is irreversible, and the irreversible dementia is also known as primary dementia and the most common one. The reversible dementia is also known as secondary dementia and caused by hormonal deficiency, vitamin deficiency, mental depression and malignancy, etc. The irreversible dementia is further subdivided into seven types are vascular dementia, dementia with Lewy bodies, mixed dementia, Parkinson s disease, frontotemporal dementia, Creutzfeldt-Jakob disease, and normal pressure hydrocephalus. Alzheimer s disease (AD) is a complex neurodegenerative disorder caused by [1] increased oxidative stress, the impaired protein-folding function of the endoplasmic reticulum, and deficient proteasome- and autophagic-mediated clearance of damaged proteins also associated with aging. AD is the common form of dementia. The accumulation of amyloid and tau proteins in AD and Access this article online Website: jprsolutions.info ISSN: the number of neurofibrillary tangles is a pathologic marker of the severity of AD. The main component of the tangles is a hyperphosphorylated and aggregated form of tau. [2] Abnormal tau fragments are cytotoxic and impair cognition. [3] β-amyloid (Aβ) formed by the continuously proteolytic processing of β-amyloid precursor protein by β-secretase and γ-secretase plays a key part in the pathogenesis of AD. [4] Short and ultra-short peptides were inhibiting aggregation of Aβ and reduce its toxic effects. It is also shown to be effective in AD rodent animal models. [5] Based on the above factor, the aim of the present study is to evaluate the β-secretase activity of short and ultra-short peptides by in silico drug design. MATERIALS AND METHODS Molecular Modeling Studies The X-ray crystal structures of beta-secretase (Figure 1: Protein Data Bank [PDB]: 3LII) retrieved from the RCSB PDB. Ligand structures of peptide analogs were constructed using the splinter dictionary of Maestro 9.3 (Schrodinger, LLC) using the optimized potentials for liquid simulations - all-atom (OPLS-AA) force fields with the steepest descent followed by curtailed Newton conjugate gradient protocol. Partial atomic charges were computed using the OPLS-AA force field. [6,7] 1 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Asian Institute of Medicine, Science and Technology, University, Bedong, Kedah Darul Aman, Malaysia, 2 Department of Pharmaceutical Chemistry, Faculty of Pharmacy, M. S. Ramaiah University of Applied Sciences, Bengaluru, Karnataka, India. *Corresponding author: Pandurangan Perumal, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Asian Institute of Medicine, Science and Technology, University, Bedong, Kedah Darul Aman, Malaysia. perupharma78@gmail.com Received on: ; Revised on: ; Accepted on:

2 Every single docking calculation has been performed using the extra precision (XP) mode of GLIDE program. The finest docked structure was preferred using a GLIDE score function. GLIDE score (G-score) takes into account a number of parameters such as hydrogen bonds (H-bond), hydrophobic contacts (Lipo), Van der Waals (vdw), coulombic (Coul), polar interactions in the binding site (Site), metal binding term (Metal), penalty for buried polar group (BuryP), and freezing rotatable bonds (RotB). G-score=H bond+lipo+metal+site+0.130coul vdW-BuryP-RotB. An additional scoring function utilized by GLIDE is E-model, which itself consequential from a combination of the G score, coulombic, Van der Waals, and the strain energy of the ligand. The ligand structures [Figure 2] were constructed using the splinter dictionary of Maestro 9.3 (Schrodinger, LLC) using the OPLS-AA force field with the steepest descent followed by curtailed Newton conjugate gradient protocol. Partial atomic charges were computed using the OPLS-AA force field. Initially, the peptide sequences de novo peptide structure was predicted using PEP-FOLD server at Mobyle server portal (bioserv.rpbs.univ-paris-diderot.fr/services/ PEP-FOLD/). Before docking the X-ray crystal structures of β-secretase (BACE1) with pdb id: 1FKN [8] was retrieved from the RCSB PDB. Their corresponding protein structures were subsequently prepared using the Protein Preparation Wizard in the Schrödinger software suite. [9] The BACE1 structure was optimized by removing the water molecules, heteroatoms, and cofactors. Hydrogen, missing atoms, bonds, and charges were computed. Further, all the peptides were docked to beta-secretase using guide peptide docking procedure. [9] Further, receptor grid was generated around the BACE1 enzyme active site by choosing centroid of BACE1 complexed octapeptide (EVNXAEF) with the grid box size set to 20 Å radius using receptor grid generation panel implemented in GLIDE. [9] All the peptides docking calculations were performed using standard precision peptide docking mode. The GLIDE docking score was used to determine the bestdocked structure from the output. The binding affinity of the BACE1/octapeptide complexes was expressed as docking scores. The interactions of these docked complexes were further analyzed using PyMOL. [10] RESULTS AND DISCUSSION The docking analysis was done for the ligands such with the target protein beta-secretase using the docking software GLIDE and the docked images are shown in Figure 2. The structures docked by GLIDE are generally ranked according to the GLIDE scoring function (more negative). The scoring function of GLIDE docking program is presented in the G-score form and is shown in Table 1. The most straightforward method of evaluating the accuracy of a docking procedure is to determine how closely the lowest energy pose (binding conformation) predicted by the object scoring function. In the present study, XP GLIDE docking procedure was validated by removing the inhibitor compound with acetylcholinesterase protein has been analyzed from the G-score, GLIDE energy, and H-bonds. The interaction energy includes Van der Waals energy, electrostatic energy, as well as intermolecular hydrogen bonding was calculated for each minimized complex. Docking score of peptides using GLIDE varied between 11.60Kcal/mol and 3.807Kcal/mol against beta-secretase and docking score of Donepezil as standard using GLIDE varied is 5.84Kcal/mol against beta-secretase. This proves that octapeptides, dipeptides, and heterocyclic dipeptide analogs could be potential drugs for anti-alzheimer drug development. The GLIDE score is capable of being used as a semiquantitative descriptor for the capability of ligands to bind to a specific conformation of the protein receptor. Conformational analysis of docked complex shows that the residues GLY 234, THR 238, ASN 233, TRP 532, ASN 233, GLU 313, PRO 235, ARG 247, and Figure 1: X-ray crystal structure of protein beta-secretase enzyme with inhibitor Table 1: Docking results of short and ultra short peptides against beta secretase (BACE1) Entry name Docking score HH I DP IV AIA II DP I AIA III DP II Donepezil 5.84 Galantamine 5.42 Tacrine 6.09 Rivastigmine

3 Figure 2: The ligand structures ARG 296 against beta-secretase play a key role in this receptor s activity. In the case of docking, the three octapeptides only HH1 was stable to bind with with docking score of , whereas HH2 and HH3 failed to dock. The binding mode of HH1 shows that the amino-terminal end residue Lys1 of the HH1 peptide side chain NH 3 + forms two hydrogen bonds with backbone oxygen and side chain OH 1878

4 Figure 3: Shows the binding mode DP1 peptide in Figure 6: Shows the binding mode AIA2 peptide in Figure 4: Shows the binding mode DP4 peptide in Figure 7: Shows the binding mode HH1 peptide (brownishyellow sticks) in. The key interacting residues are shown in green color lines and the hydrogen bonds are represented as yellow dashed lines Figure 5: Shows the binding mode DP2 peptide in of Thr329 of BACE1. Moreover, Lys1 side chain aliphatic alkane also forms hydrophobic interaction with Ile226. In addition, the Lys1 backbone oxygen forms hydrogen bond with Thr72 backbone NH. The HH1 peptide residue Phe2 backbone NH forms hydrogen bond with OH of Tyr198 side chain. The docking score of the peptides (AIA II, DP1, AIA III, and DP II) against beta-secretase enzyme was found to be highly potent 8.645, 7.483, 6.919, and than standard donepezil 5.84 [Figures 1, 3-8]. CONCLUSION In silico docking study was done for the designed short and ultra-short peptides against beta-secretase enzyme shows highly significance binding affinity toward HH1, DP IV, and AIA II peptides. The result showed that HH1, DP IV, and AIA II exhibited more capability to inhibit BACE1 enzyme. Figure 8: Standard donepezil REFERENCES 1. Ghosh AK, Kumaragurubaran N, Tang J. Recent developments of structure based beta-secretase inhibitors for alzheimer s disease. Curr Top Med Chem 2005;5: Querfurth HW, Frank M, Ferla L. Mechanisms of disease -alzheimer s disease. N Engl J Med 2010;362: Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, Jones G, et al. Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP. Science 2001;293: John V, Beck JP, Bienkowski MJ, Sinha S, Heinrikson RL. Human beta-secretase (BACE) and BACE inhibitors. J Med Chem 2003;46: Funke SA, Willbold D. Peptides for therapy and diagnosis of alzheimer s disease. Curr Pharm Des 2012;18: Perumal P, Chigurupati S, Selvaraj M. Anticholinesterase activity of octa peptides related to human histatin 8: In-silico drug design and In-vitro. Asian J Pharm Clin Res 2017;10:

5 7. Perumal P, Pandey VP. Docking studies on antimicrobial peptides related to APIDAECIN- IA and human histatin against glutamine synthetase and RNA polymerase in Mycobacterium tuberculosis. Asian J Pharm Clin Res 2014;7: Hong L, Koelsch G, Lin X, Wu S, Terzyan S, Ghosh AK, et al. Structure of the protease domain of memapsin 2 (betasecretase) complexed with inhibitor. Science 2000;290: Schrodinger, LLC. Schrodinger Release : Maestro, Ver New York: Schrodinger, LLC; Schrodinger LCC. PyMOL Molecular Graphics System. NY, USA: Schrodinger LCC; Source of support: Nil; Conflict of interest: None Declared 1880