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Unraveling the Structural Dynamics of an Enzyme Encapsulated within a Metal-Organic Framework

Tuan Kob TNA, Ismail MF, Abdul Rahman MB, Cordova KE, Mohammad Latif MA

J Phys Chem B, 2020 05 07;124(18):3678-3685.
PMID: 32275422 DOI: 10.1021/acs.jpcb.0c02145

Herein, we detail an atomic-level investigation of the cutinase enzyme encapsulated within a model metal-organic framework (MOF) platform using quantum mechanics calculations and molecular dynamics simulations. Cutinase, when encapsulated in an isoreticularly expanded MOF-74 (cutinase@IRMOF-74-VI), was proven to maintain its structural stability at temperatures that would otherwise denature the enzyme in its unprotected native state. Hydrogen bonding and salt bridge interactions, most notably involving arginine residues at the surface of the enzyme, were critical for stabilizing cutinase within the pore channels of IRMOF-74-VI. The findings reported support the viability of enzyme encapsulation in a porous material by demonstrating that a model enzyme not only retains its structural integrity but also remains accessible and active under extreme and foreign conditions.
Fulltext Inhibitory evaluation of Curculigo latifolia on α-glucosidase, DPP (IV) and in vitro studies in antidiabetic with molecular docking relevance to type 2 diabetes mellitus

Zabidi NA, Ishak NA, Hamid M, Ashari SE, Mohammad Latif MA

J Enzyme Inhib Med Chem, 2021 Dec;36(1):109-121.
PMID: 33249946 DOI: 10.1080/14756366.2020.1844680

The inhibition of α-glucosidase and DPP enzymes capable of effectively reducing blood glucose level in the management of type 2 diabetes. The purpose of the present study is to evaluate the inhibitory potential of α-glucosidase and DPP (IV) activity including with the 2-NBDG uptake assay and insulin secretion activities through in vitro studies. The selected of active compounds obtained from the screening of compounds by LC-MS were docked with the targeted enzyme that involved in the mechanism of T2DM. From the results, root extracts displayed a better promising outcome in α-glucosidase (IC50 2.72 ± 0.32) as compared with the fruit extracts (IC50 3.87 ± 0.32). Besides, root extracts also displayed a better activity in the inhibition of DPP (IV), enhance insulin secretion and glucose uptake activity. Molecular docking results revealing that phlorizin binds strongly with α-glucosidase, DPP (IV) and Insulin receptor (IR) enzymes with achieving the lowest binding energy value. The present work suggests several of the compounds have the potential that contribute towards inhibiting α-glucosidase and DPP (IV) and thus effective in lowering post-prandial hyperglycaemia.
Fulltext Preliminary Insight of Pyrrolylated-Chalcones as New Anti-Methicillin-Resistant Staphylococcus aureus (Anti-MRSA) Agents

Gunasekharan M, Choi TI, Rukayadi Y, Mohammad Latif MA, Karunakaran T, Mohd Faudzi SM, et al.

Molecules, 2021 Sep 01;26(17).
PMID: 34500755 DOI: 10.3390/molecules26175314

Bacterial infections are regarded as one of the leading causes of fatal morbidity and death in patients infected with diseases. The ability of microorganisms, particularly methicillin-resistant Staphylococcus aureus (MRSA), to develop resistance to current drugs has evoked the need for a continuous search for new drugs with better efficacies. Hence, a series of non-PAINS associated pyrrolylated-chalcones (1-15) were synthesized and evaluated for their potency against MRSA. The hydroxyl-containing compounds (8, 9, and 10) showed the most significant anti-MRSA efficiency, with the MIC and MBC values ranging from 0.08 to 0.70 mg/mL and 0.16 to 1.88 mg/mL, respectively. The time-kill curve and SEM analyses exhibited bacterial cell death within four hours after exposure to 9, suggesting its bactericidal properties. Furthermore, the docking simulation between 9 and penicillin-binding protein 2a (PBP2a, PDB ID: 6Q9N) suggests a relatively similar bonding interaction to the standard drug with a binding affinity score of -7.0 kcal/mol. Moreover, the zebrafish model showed no toxic effects in the normal embryonic development, blood vessel formation, and apoptosis when exposed to up to 40 µM of compound 9. The overall results suggest that the pyrrolylated-chalcones may be considered as a potential inhibitor in the design of new anti-MRSA agents.
Fulltext Exploring the Potential of a Highly Scalable Metal-Organic Framework CALF-20 for Selective Gas Adsorption at Low Pressure

Borzehandani MY, Jorabchi MN, Abdulmalek E, Abdul Rahman MB, Mohammad Latif MA

Polymers (Basel), 2023 Feb 02;15(3).
PMID: 36772061 DOI: 10.3390/polym15030760

In this study, the ability of the highly scalable metal-organic framework (MOF) CALF-20 to adsorb polar and non-polar gases at low pressure was investigated using grand canonical Monte Carlo (GCMC) and molecular dynamics (MD) simulations. The results from the simulated adsorption isotherms revealed that the highest loading was achieved for SO2 and Cl2, while the lowest loading was found for F2 molecules. The analysis of interaction energies indicated that SO2 molecules were able to form the strongest adsorbent-adsorbate interactions and had a tight molecular packing due to their polarity and angular structure. Additionally, Cl2 gas was found to be highly adsorbed due to its large van der Waals surface and strong chemical affinity in CALF-20 pores. MD simulations showed that SO2 and Cl2 had the lowest mobility inside CALF-20 pores. The values of the Henry coefficient and isosteric heat of adsorption confirmed that CALF-20 could selectively adsorb SO2 and Cl2. Based on the results, it was concluded that CALF-20 is a suitable adsorbent for SO2 and Cl2 but not for F2. This research emphasizes the importance of molecular size, geometry, and polarity in determining the suitability of a porous material as an adsorbent for specific adsorbates.
Bioinspired mp20 mimicking uricase in ZIF-8: Metal ion dependent for controllable activity

Abdul Aziz SFN, Salleh AB, Normi YM, Mohammad Latif MA, Alang Ahmad SA

Enzyme Microb Technol, 2024 Mar 21;178:110439.
PMID: 38579423 DOI: 10.1016/j.enzmictec.2024.110439

Mini protein mimicking uricase (mp20) has shown significant potential as a replacement for natural enzymes in the development of uric acid biosensors. However, the design of mp20 has resulted to an inactive form of peptide, causing of loss their catalytic activity. Herein, this paper delineates the impact of various metal cofactors on the catalytic activity of mp20. The metal ion-binding site prediction and docking (MIB) web server was employed to identify the metal ion binding sites and their affinities towards mp20 residues. Among the tested metal ions, Cu2+ displayed the highest docking score, indicating its preference for interaction with Thr16 and Asp17 residues of mp20. To assess the catalytic activity of mp20 in the presence of metal ions, uric acid assays was monitored using a colorimetric method. The presence of Cu2+ in the assays promotes the activation of mp20, resulting in a color change based on quinoid production. Furthermore, the encapsulation of the mp20 within zeolitic imidazolate framework-8 (ZIF-8) notably improved the stability of the biomolecule. In comparison to the naked mp20, the encapsulated ZIFs biocomposite (mp20@ZIF-8) demonstrates superior stability, selectivity and sensitivity. ZIF's porous shells provides excellent protection, broad detection (3-100 μM) with a low limit (4.4 μM), and optimal function across pH (3.4-11.4) and temperature (20-100°C) ranges. Cost-effective and stable mp20@ZIF-8 surpasses native uricase, marking a significant biosensor technology breakthrough. This integration of metal cofactor optimization and robust encapsulation sets new standards for biosensing applications.
Effects of anthocyanidins on the conformational transition of Aβ(1-42) peptide: Insights from molecular docking and molecular dynamics simulations

Zakaria N, Wan Harun WMRS, Mohammad Latif MA, Azaman SNA, Abdul Rahman MB, Faujan NH

J Mol Graph Model, 2024 Jun;129:108732.
PMID: 38412813 DOI: 10.1016/j.jmgm.2024.108732

Recent evidence from in vitro and in vivo studies has shown that anthocyanins and anthocyanidins can reduce and inhibit the amyloid beta (Aβ) species, one of the hallmarks of Alzheimer's disease (AD). However, their inhibition mechanisms on Aβ species at molecular details remain elusive. Therefore, in the present study, molecular modelling methods were employed to investigate their inhibitory mechanisms on Aβ(1-42) peptide. The results highlighted that anthocyanidins effectively inhibited the conformational transitions of helices into beta-sheet (β-sheet) conformation within Aβ(1-42) peptide by two different mechanisms: 1) the obstruction of two terminals from coming into contact due to the binding of anthocyanidins with residues of N- and second hydrophobic core (SHC)-C-terminals, and 2) the prevention of the folding process due to the binding of anthocyanidin with the central polar (Asp23 and Lys28) and native helix (Asp23, Lys28, and Leu34) residues. These new findings on the inhibition of β-sheet formation by targeting both N- and SHC-C-terminals, and the long-established target, D23-K28 salt bridge residues, not with the conventional central hydrophobic core (CHC) as reported in the literature, might aid in designing more potent inhibitors for AD treatment.
Fulltext α-Amylase and dipeptidyl peptidase-4 (DPP-4) inhibitory effects of Melicope latifolia bark extracts and identification of bioactive constituents using in vitro and in silico approaches

Quek A, Kassim NK, Lim PC, Tan DC, Mohammad Latif MA, Ismail A, et al.

Pharm Biol, 2021 Dec;59(1):964-973.
PMID: 34347568 DOI: 10.1080/13880209.2021.1948065

CONTEXT: Melicope latifolia (DC.) T. G. Hartley (Rutaceae) was reported to contain various phytochemicals including coumarins, flavonoids, and acetophenones.
OBJECTIVE: This study investigates the antidiabetic and antioxidant effects of M. latifolia bark extracts, fractions, and isolated constituents.
MATERIALS AND METHODS: Melicope latifolia extracts (hexane, chloroform, and methanol), fractions, and isolated constituents with varying concentrations (0.078-10 mg/mL) were subjected to in vitro α-amylase and dipeptidyl peptidase-4 (DPP-4) inhibitory assay. Molecular docking was performed to study the binding mechanism of active compounds towards α-amylase and DPP-4 enzymes. The antioxidant activity of M. latifolia fractions and compounds were determined by 2,2-diphenyl-1-picrylhydrazyl (DPPH) free radical scavenging and β-carotene bleaching assays.
RESULTS: Melicope latifolia chloroform extract showed the highest antidiabetic activity (α-amylase IC50: 1464.32 μg/mL; DPP-4 IC50: 221.58 μg/mL). Fractionation of chloroform extract yielded four major fractions (CF1-CF4) whereby CF3 showed the highest antidiabetic activity (α-amylase IC50: 397.68 μg/mL; DPP-4 IC50: 37.16 μg/mL) and resulted in β-sitosterol (1), halfordin (2), methyl p-coumarate (3), and protocatechuic acid (4). Isolation of compounds 2-4 from the species and their DPP-4 inhibitory were reported for the first time. Compound 2 showed the highest α-amylase (IC50: 197.53 μM) and β-carotene (88.48%) inhibition, and formed the highest number of molecular interactions with critical amino acid residues of α-amylase. The highest DPP-4 inhibition was exhibited by compound 3 (IC50: 911.44 μM).
DISCUSSION AND CONCLUSIONS: The in vitro and in silico analyses indicated the potential of M. latifolia as an alternative source of α-amylase and DPP-4 inhibitors. Further pharmacological studies on the compounds are recommended.
Development of diarylpentadienone analogues as alpha-glucosidase inhibitor: Synthesis, in vitro biological and in vivo toxicity evaluations, and molecular docking analysis

Abdullah MA, Lee YR, Mastuki SN, Leong SW, Wan Ibrahim WN, Mohammad Latif MA, et al.

Bioorg Chem, 2020 11;104:104277.
PMID: 32971414 DOI: 10.1016/j.bioorg.2020.104277

A series of aminated- (1-9) and sulfonamide-containing diarylpentadienones (10-18) were synthesized, structurally characterized, and evaluated for their in vitro anti-diabetic potential on α-glucosidase and DPP-4 enzymes. It was found that all the new molecules were non-associated PAINS compounds. The sulfonamide-containing series (compounds 10-18) selectively inhibited α-glucosidase over DPP-4, in which compound 18 demonstrated the highest activity with an IC50 value of 5.69 ± 0.5 µM through a competitive inhibition mechanism. Structure-activity relationship (SAR) studies concluded that the introduction of the trifluoromethylbenzene sulfonamide moiety was essential for the suppression of α-glucosidase. The most active compound 18, was then further tested for in vivo toxicities using the zebrafish animal model, with no toxic effects detected in the normal embryonic development, blood vessel formation, and apoptosis of zebrafish. Docking simulation studies were also carried out to better understand the binding interactions of compound 18 towards the homology modeled α -glucosidase and the human lysosomal α -glucosidase enzymes. The overall results suggest that the new sulfonamide-containing diarylpentadienones, compound 18, could be a promising candidate in the search for a new α-glucosidase inhibitor, and can serve as a basis for further studies involving hit-to-lead optimization, in vivo efficacy and safety assessment in an animal model and mechanism of action for the treatment of T2DM patients.