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Highly Efficient Deacidification of High-Acid Rice Bran Oil Using Methanol as a Novel Acyl Acceptor

Li D, Faiza M, Ali S, Wang W, Tan CP, Yang B, et al.

Appl Biochem Biotechnol, 2018 Apr;184(4):1061-1072.
PMID: 28948493 DOI: 10.1007/s12010-017-2594-1

A highly efficient process for reducing the fatty acid (FA) content of high-acid rice bran oil (RBO) was developed by immobilized partial glycerides-selective lipase SMG1-F278N-catalyzed esterification/transesterification using methanol as a novel acyl acceptor. Molecular docking simulation indicated that methanol was much closer to the catalytic serine (Ser-171) compared with ethanol and glycerol, which might be one of the reasons for its high efficiency in the deacidification of high-acid RBO. Additionally, the reaction parameters were optimized to minimize the FA content of high-acid RBO. Under the optimal conditions (substrate molar ratio of methanol to FAs of 1.8:1, enzyme loading of 40 U/g, and at 30 °C), FA content decreased from 25.14 to 0.03% after 6 h of reaction. Immobilized SMG1-F278N exhibited excellent methanol tolerance and retained almost 100% of its initial activity after being used for ten batches. After purification by molecular distillation, the final product contained 97.86% triacylglycerol, 2.10% diacylglycerol, and 0.04% FA. The acid value of the final product was 0.09 mg KOH/g, which reached the grade one standard of edible oil. Overall, methanol was a superior acyl acceptor for the deacidification of high-acid RBO and the high reusability of immobilized SMG1-F278N indicates an economically attractive process.

Matched MeSH terms: Molecular Docking Simulation*
Characterization and antiinflammatory properties of fractionated pyroligneous acid from palm kernel shell

Rabiu Z, Hamzah MAAM, Hasham R, Zakaria ZA

Environ Sci Pollut Res Int, 2021 Aug;28(30):40535-40543.
PMID: 32418105 DOI: 10.1007/s11356-020-09209-x

Pyroligneous acid (PA) obtained from slow pyrolysis of palm kernel shell (PKS) has high total phenolic contents and exhibits various biological activities including antioxidant, antibacterial and antifungal. In this study, PA obtained using slow pyrolysis method and fractionated using column chromatography was characterized (chemical and antioxidative properties) and investigated for its cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) inhibition activities using the in vitro and in silico approaches. The F9 PA fraction exhibited highest total phenolic content of 181.75 ± 17.0 μg/mL. Fraction F21-25 showed ferric reducing antioxidant power (FRAP) (331.80 ± 4.60 mg TE/g) and IC50 of 18.56 ± 0.01 μg/mL towards COX-2 and 5.25 ± 0.03 μg/mL towards the 5-LOX enzymes, respectively. Molecular docking analysis suggested favourable binding energy for all chemical compounds present in fraction F21-25, notably 1-(2,4,6-trihydroxyphenyl)-2-pentanone, towards both COX-2 (- 6.9 kcal/mol) and 5-LOX (- 6.4 kcal/mol) enzymes. As a conclusion, PA from PKS has the potential to be used as an alternative antioxidant and antiinflammatory agents which is biodegradable and a more sustainable supply of raw materials.

Matched MeSH terms: Molecular Docking Simulation
In silico screening of plant peptides against the envelope protein of dengue virus

Reena G, Ranjani R, Goutham KD, Sangeetha K

Trop Biomed, 2023 Jun 01;40(2):124-128.
PMID: 37650397 DOI: 10.47665/tb.40.2.001

Peptide therapeutics are found to be an emerging and attractive class of treatment due to their highly specific and safe nature. Hence twenty plant peptides were subjected to screening by molecular docking against the envelope protein of the dengue virus using Clus Pro, Patch Dock, and HADDOCK servers. Physicochemical parameters, allergenicity, and toxicity profile of the plant peptides were estimated by Protparam analysis, AllergenFP, and ToxinPred web servers. Six potential compounds namely Ginkbilobin, Cycloviolin-D, Circulin-B, Circulin-A, Cycloviolacin-013, and Circulin-C showed the highest binding energy with both nonallergenic and nontoxic properties. They also exhibited desirable half-lives extending to 30 hrs except for Ginkbilobin, which showed the least half-life of 4.4 hours and non-polar activity. The residues of Ala-4 of Ginkbilobin; Arg-30 of Cycloviolin D; Arg-29 of Circulin A and C interacted with the Try 101 of the domain II of Envelope protein, implying the possible inhibition of the insertion process of the trimeric E protein during fusion with the host cells. Thus, the identified plant peptides could serve as potential leads upon further subjection to in vitro studies.

Matched MeSH terms: Molecular Docking Simulation
Fulltext Macrolactin A as a Novel Inhibitory Agent for SARS-CoV-2 Mpro: Bioinformatics Approach

Bharadwaj KK, Sarkar T, Ghosh A, Baishya D, Rabha B, Panda MK, et al.

Appl Biochem Biotechnol, 2021 Oct;193(10):3371-3394.
PMID: 34212286 DOI: 10.1007/s12010-021-03608-7

COVID-19 is a disease that puts most of the world on lockdown and the search for therapeutic drugs is still ongoing. Therefore, this study used in silico screening to identify natural bioactive compounds from fruits, herbaceous plants, and marine invertebrates that are able to inhibit protease activity in SARS-CoV-2 (PDB: 6LU7). We have used extensive screening strategies such as drug likeliness, antiviral activity value prediction, molecular docking, ADME, molecular dynamics (MD) simulation, and MM/GBSA. A total of 17 compounds were shortlisted using Lipinski's rule in which 5 compounds showed significant predicted antiviral activity values. Among these 5, only 2 compounds, Macrolactin A and Stachyflin, showed good binding energy of -9.22 and -8.00 kcal/mol, respectively, within the binding pocket of the Mpro catalytic residues (HIS 41 and CYS 145). These two compounds were further analyzed to determine their ADME properties. The ADME evaluation of these 2 compounds suggested that they could be effective in developing therapeutic drugs to be used in clinical trials. MD simulations showed that protein-ligand complexes of Macrolactin A and Stachyflin with the target receptor (6LU7) were stable for 100 nanoseconds. The MM/GBSA calculations of Mpro-Macrolactin A complex indicated higher binding free energy (-42.58 ± 6.35 kcal/mol). Dynamic cross-correlation matrix (DCCM) and principal component analysis (PCA) on the residual movement in the MD trajectories further confirmed the stability of Macrolactin A bound state with 6LU7. In conclusion, this study showed that marine natural compound Macrolactin A could be an effective therapeutic inhibitor against SARS-CoV-2 protease (6LU7). Additional in vitro and in vivo validations are strongly needed to determine the efficacy and therapeutic dose of Macrolactin A in biological systems.

Matched MeSH terms: Molecular Docking Simulation*
Combination mode of antimalarial drug mefloquine and human serum albumin: Insights from spectroscopic and docking approaches

Musa KA, Ridzwan NFW, Mohamad SB, Tayyab S

Biopolymers, 2020 Feb;111(2):e23337.
PMID: 31691964 DOI: 10.1002/bip.23337

The interaction between mefloquine (MEF), the antimalarial drug, and human serum albumin (HSA), the main carrier protein in blood circulation, was explored using fluorescence, absorption, and circular dichroism spectroscopic techniques. Quenching of HSA fluorescence with MEF was characterized as static quenching and thus confirmed the complex formation between MEF and HSA. Association constant values for MEF-HSA interaction were found to fall within the range of 3.79-5.73 × 104 M-1 at various temperatures (288, 298, and 308 K), which revealed moderate binding affinity. Hydrogen bonds and hydrophobic interactions were predicted to connect MEF and HSA together in the MEF-HSA complex, as deduced from the thermodynamic data (ΔS = +133.52 J mol-1 K-1 and ΔH = +13.09 kJ mol-1 ) of the binding reaction and molecular docking analysis. Three-dimensional fluorescence spectral analysis pointed out alterations in the microenvironment around aromatic amino acid (tryptophan and tyrosine) residues of HSA consequent to the addition of MEF. Circular dichroic spectra of HSA in the wavelength ranges of 200-250 and 250-300 nm hinted smaller changes in the protein's secondary and tertiary structures, respectively, induced by MEF binding. Noncovalent conjugation of MEF to HSA bettered protein thermostability. Site marker competitive drug displacement results suggested HSA Sudlow's site I as the MEF binding site, which was also supported by molecular docking analysis.

Matched MeSH terms: Molecular Docking Simulation*
Infrared spectrum, NBO, HOMO-LUMO, MEP and molecular docking studies (2E)-3-(3-nitrophenyl)-1-[4-piperidin-1-yl]prop-2-en-1-one

Panicker CY, Varghese HT, Nayak PS, Narayana B, Sarojini BK, Fun HK, et al.

Spectrochim Acta A Mol Biomol Spectrosc, 2015 Sep 5;148:18-28.
PMID: 25863456 DOI: 10.1016/j.saa.2015.03.065

FT-IR spectrum of (2E)-3-(3-nitrophenyl)-1-[4-piperidin-1-yl]prop-2-en-1-one was recorded and analyzed. The vibrational wavenumbers were computed using HF and DFT quantum chemical calculations. The data obtained from wavenumber calculations are used to assign IR bands. Potential energy distribution was done using GAR2PED software. The geometrical parameters of the title compound are in agreement with the XRD results. NBO analysis, HOMO-LUMO, first and second hyperpolarizability and molecular electrostatic potential results are also reported. The possible electrophile attacking sites of the title molecule is identified using MEP surface plot study. Molecular docking results predicted the anti-leishmanic activity for the compound.

Matched MeSH terms: Molecular Docking Simulation
Molecular docking and molecular dynamics simulations of a mutant Acinetobacter haemolyticus alkaline-stable lipase against tributyrin

Anuar NFSK, Wahab RA, Huyop F, Amran SI, Hamid AAA, Halim KBA, et al.

J Biomol Struct Dyn, 2021 Apr;39(6):2079-2091.
PMID: 32174260 DOI: 10.1080/07391102.2020.1743364

We previously reported on a mutant lipase KV1 (Mut-LipKV1) from Acinetobacter haemolyticus which optimal pH was raised from 8.0 to 11.0 after triple substitutions of surface aspartic acid (Asp) with lysine (Lys). Herein, this study further examined the Mut-LipKV1 by molecular docking, molecular dynamics (MD) simulations and molecular mechanics-Poisson Boltzmann surface area (MM-PBSA) calculations to explore the structural requirements that participated in the effective binding of tributyrin and its catalytic triad (Ser165, Asp259 and His289) and identify detailed changes that occurred post mutation. Mut-LipKV1 bound favorably with tributyrin (-4.1 kcal/mol) and formed a single hydrogen bond with His289, at pH 9.0. Despite the incongruent docking analysis data, results of MD simulations showed configurations of both the tributyrin-Mut-LipKV1 (RMSD 0.3 nm; RMSF 0.05 - 0.3 nm) and the tributyrin-wildtype lipase KV1 (tributyrin-LipKV1) complexes (RMSD 0.35 nm; RMSF 0.05 - 0.4 nm) being comparably stable at pH 8.0. MM-PBSA analysis indicated that van der Waals interactions made the most contribution during the molecular binding process, with the Mut-LipKV1-tributyrin complex (-44.04 kcal/mol) showing relatively lower binding energy than LipKV1-tributyrin (-43.83 kcal/mol), at pH 12.0. All tributyrin-Mut-LipKV1 complexes displayed improved binding free energies over a broader pH range from 8.0 - 12.0, as compared to LipKV1-tributyrin. Future empirical works are thus, important to validate the improved alkaline-stability of Mut-LipKV1. In a nutshell, our research offered a considerable insight for further improving the alkaline tolerance of lipases.Communicated by Ramaswamy H. Sarma.

Matched MeSH terms: Molecular Docking Simulation
An experimental and theoretical study on the interaction of DNA and BSA with novel Ni2+, Cu2+ and VO2+ complexes derived from vanillin bidentate Schiff base ligand

Dostani M, Kianfar AH, Mahmood WA, Dinari M, Farrokhpour H, Sabzalian MR, et al.

Spectrochim Acta A Mol Biomol Spectrosc, 2017 Jun 05;180:144-153.
PMID: 28284160 DOI: 10.1016/j.saa.2017.02.047

In this investigation, the structure of bidentate N,N-Schiff base ligand of vanillin, (E)-4-(((2-amino-5-nitrophenyl)imino)methyl)-2-methoxyphenol (HL) was determined by single crystal X-ray diffraction. The interaction of new [CuL2], [NiL2] and [VOL2] complexes with DNA and BSA was explored through UV-Vis and fluorescence spectroscopy. The electronic spectra changes displayed an isosbestic point for the complexes upon titration with DNA. The Kb values for the complexes [CuL2], [NiL2] and [VOL2] were 2.4×105, 1.9×105 and 4.2×104, respectively. [CuL2] complex was bound more toughly than [NiL2] and [VOL2] complexes. These complexes had a significant interaction with Bovine Serum Albumin (BSA) and the results demonstrated that the quenching mechanism was a static procedure. Also, the complexes interacted with BSA by more than one binding site (n>1). Finally, the theoretical studies were performed using the docking method to calculate the binding constants and recognize the binding site of the DNA and BSA with the complexes. The ligand and complexes including Ni2+, Cu2+ and VO2+ ions were colonized by fungal growth.

Matched MeSH terms: Molecular Docking Simulation
Acetogenins Exhibit Potential BCL-XL Inhibitor for the Induction of Apoptosis in the Molecular Docking Study

Nordin N, Khimani K, Abd Ghani MF

Curr Drug Discov Technol, 2021;18(6):e010921191171.
PMID: 33563198 DOI: 10.2174/1570163818666210204202426

BACKGROUND: Anti-apoptotic protein BCL-XL plays a vital role in tumorigenesis and cancer chemotherapy resistance, resulting in a good target for cancer treatment. Understanding the function of BCL-XL has driven the progression of a new class of cancer drugs that can mimic its natural inhibitors, BH3-only proteins, to trigger apoptosis. This mimicking is initiated through acetogenins due to their excellent biological properties. Acetogenins, which can be isolated from Annonaceae plants, have a unique structure along with several oxygenated functionalities.
OBJECTIVE: Based on their biological capability, various acetogenins were studied in the present study and compared alongside ABT-737 on molecular docking.
METHODS: The docking simulation of acetogenins was performed using AutoDock Vina software.
RESULTS: Our findings have shown eleven acetogenins-BCL-XL protein complex, namely, muricin B (2), muricin F (4), muricin H (6), muricin I (7), xylomaticin (9), annomontacin (12), annonacin (14), squamocin (15), squamostatin A (16), bullatacin (20) and annoreticulin (21) exhibited strong binding affinities lower than - 10.4 kcalmol-1 as compared to ABT-373-BCL-XL complex. Six hydrogen bonds along with hydrophobic interaction were detected on the complex of BCL-XL with muricin B (2), muricin G (5), corossolone (11), and isoannonacin-10-one A (18).
CONCLUSION: These findings indicated that some acetogenins could represent a new potential BCLXL inhibitor that could mimic the BH3-only protein for the induction of apoptosis in cancer chemotherapy.

Matched MeSH terms: Molecular Docking Simulation
Synthesis, β-glucuronidase inhibition and molecular docking studies of cyano-substituted bisindole hydrazone hybrids

Abid O, Imran S, Taha M, Ismail NH, Jamil W, Kashif SM, et al.

Mol Divers, 2021 May;25(2):995-1009.
PMID: 32301032 DOI: 10.1007/s11030-020-10084-4

The β-glucuronidase, a lysosomal enzyme, catalyzes the cleavage of glucuronosyl-O-bonds. Its inhibitors play a significant role in different medicinal therapies as they cause a decrease in carcinogen-induced colonic tumors by reducing the level of toxic substances present in the intestine. Among those inhibitors, bisindole derivatives had displayed promising β-glucuronidase inhibition activity. In the current study, hydrazone derivatives of bisindolymethane (1-30) were synthesized and evaluated for in vitro β-glucuronidase inhibitory activity. Twenty-eight analogs demonstrated better activity (IC50 = 0.50-46.5 µM) than standard D-saccharic acid 1,4-lactone (IC50 = 48.4 ± 1.25 µM). Compounds with hydroxyl group like 6 (0.60 ± 0.01 µM), 20 (1.50 ± 0.10 µM) and 25 (0.50 ± 0.01 µM) exhibited the most potent inhibitory activity, followed by analogs with fluorine 21 (3.50 ± 0.10 µM) and chlorine 23 (8.20 ± 0.20 µM) substituents. The presence of hydroxyl group at the aromatic side chain was observed as the main contributing factor in the inhibitory potential. From the docking studies, it was predicted that the active compounds can fit properly in the binding groove of the β-glucuronidase and displayed significant binding interactions with essential residues.

Matched MeSH terms: Molecular Docking Simulation
Pharmacophore Modelling and Virtual Screening Studies for the Discovery of Potential Natural Products Based PDE1B Inhibitor Lead Compounds

Shy TW, Gaurav A

Cent Nerv Syst Agents Med Chem, 2021;21(3):195-204.
PMID: 34970959 DOI: 10.2174/1871524922666211231115638

AIM: The aim of the present study was to apply pharmacophore based virtual screening to a natural product database to identify potential PDE1B inhibitor lead compounds for neurodegenerative and neuropsychiatric disorders.
BACKGROUND: Neurodegenerative and neuropsychiatric disorders are a major health burden globally. The existing therapies do not provide optimal relief and are associated with substantial adverse effects. This has resulted in a huge unmet medical need for newer and more effective therapies for these disorders. Phosphodiesterase (PDEs) enzymes have been identified as potential targets of drugs for neurodegenerative and neuropsychiatric disorders, and one of the subtypes, i.e., PDE1B, accounts for more than 90 % of total brain PDE activity associated with learning and memory process, making it an interesting drug target for the treatment of neurodegenerative disorders.
OBJECTIVES: The present study has been conducted to identify potential PDE1B inhibitor lead compounds from the natural product database.
METHODS: Ligand-based pharmacophore models were generated and validated; they were then employed for virtual screening of Universal Natural Products Database (UNPD) followed by docking with PDE1B to identify the best hit compound.
RESULTS: Virtual screening led to the identification of 85 compounds which were then docked into the active site of PDE1B. Out of the 85 compounds, six showed a higher affinity for PDE1B than the standard PDE1B inhibitors. The top scoring compound was identified as Cedreprenone.
CONCLUSION: Virtual screening of UNPD using Ligand based pharmacophore led to the identification of Cedreprenone, a potential new natural PDE1B inhibitor lead compound.

Matched MeSH terms: Molecular Docking Simulation
Computational Approaches in the Discovery and Development of Therapeutic and Prophylactic Agents for Viral Diseases

Gaurav A, Agrawal N, Al-Nema M, Gautam V

Curr Top Med Chem, 2022;22(26):2190-2206.
PMID: 36278463 DOI: 10.2174/1568026623666221019110334

Over the last two decades, computational technologies have played a crucial role in antiviral drug development. Whenever a virus spreads and becomes a threat to global health, it brings along the challenge of developing new therapeutics and prophylactics. Computational drug and vaccine discovery has evolved quickly over the years. Some interesting examples of computational drug discovery are anti-AIDS drugs, where HIV protease and reverse transcriptase have been targeted by agents developed using computational methods. Various computational methods that have been applied to anti-viral research include ligand-based methods that rely on known active compounds, i.e., pharmacophore modeling, machine learning or classical QSAR; structure-based methods that rely on an experimentally determined 3D structure of the targets, i.e., molecular docking and molecular dynamics and methods for the development of vaccines such as reverse vaccinology; structural vaccinology and vaccine epitope prediction. This review summarizes these approaches to battle viral diseases and underscores their importance for anti-viral research. We discuss the role of computational methods in developing small molecules and vaccines against human immunodeficiency virus, yellow fever, human papilloma virus, SARS-CoV-2, and other viruses. Various computational tools available for the abovementioned purposes have been listed and described. A discussion on applying artificial intelligence-based methods for antiviral drug discovery has also been included.

Matched MeSH terms: Molecular Docking Simulation
Sustainable lignocellulose fractionation by integrating p-toluenesulfonic acid/pentanol pretreatment with mannitol for efficient production of glucose, native-like lignin, and furfural

Madadi M, Elsayed M, Sun F, Wang J, Karimi K, Song G, et al.

Bioresour Technol, 2023 Mar;371:128591.
PMID: 36627085 DOI: 10.1016/j.biortech.2023.128591

A new cutting-edge lignocellulose fractionation technology for the co-production of glucose, native-like lignin, and furfural was introduced using mannitol (MT)-assisted p-toluenesulfonic acid/pentanol pretreatment, as an eco-friendly process. The addition of optimized 5% MT in pretreatment enhanced the delignification rate by 29% and enlarged the surface area and biomass porosity by 1.07-1.80 folds. This increased the glucose yield by 45% (from 65.34 to 94.54%) after enzymatic hydrolysis relative to those without MT. The extracted lignin in the organic phase of pretreatment exhibited β-O-4 bonds (61.54/100 Ar) properties of native cellulosic enzyme lignin. Lignin characterization and molecular docking analyses revealed that the hydroxyl tails of MT were incorporated with lignin and formed etherified lignin, which preserved high lignin integrity. The solubilized hemicellulose (96%) in the liquid phase of pretreatment was converted into furfural with a yield of 83.99%. The MT-assisted pretreatment could contribute to a waste-free biorefinery pathway toward a circular bioeconomy.

Matched MeSH terms: Molecular Docking Simulation
An integrated assessment of ecological and human health risks of per- and polyfluoroalkyl substances through toxicity prediction approaches

Hamid N, Junaid M, Manzoor R, Sultan M, Chuan OM, Wang J

Sci Total Environ, 2023 Dec 20;905:167213.
PMID: 37730032 DOI: 10.1016/j.scitotenv.2023.167213

Per- and polyfluoroalkyl substances (PFAS) are also known as "forever chemicals" due to their persistence and ubiquitous environmental distribution. This review aims to summarize the global PFAS distribution in surface water and identify its ecological and human risks through integrated assessment. Moreover, it provides a holistic insight into the studies highlighting the human biomonitoring and toxicological screening of PFAS in freshwater and marine species using quantitative structure-activity relationship (QSAR) based models. Literature showed that PFOA and PFOS were the most prevalent chemicals found in surface water. The highest PFAS levels were reported in the US, China, and Australia. The TEST model showed relatively low LC50 of PFDA and PFOS for Pimephales promelas (0.36 and 0.91 mg/L) and high bioaccumulation factors (518 and 921), revealing an elevated associated toxicity. The risk quotients (RQs) values for P. promelas and Daphnia magna were found to be 269 and 23.7 for PFOS. Studies confirmed that long-chain PFAS such as PFOS and PFOA undergo bioaccumulation in aquatic organisms and induce toxicological effects such as oxidative stress, transgenerational epigenetic effects, disturbed genetic and enzymatic responses, perturbed immune system, hepatotoxicity, neurobehavioral toxicity, altered genetic and enzymatic responses, and metabolism abnormalities. Human biomonitoring studies found the highest PFOS, PFOA, and PFHxS levels in urine, cerebrospinal fluid, and serum samples. Further, long-chain PFOA and PFOS exposure create severe health implications such as hyperuricemia, reduced birth weight, and immunotoxicity in humans. Molecular docking analysis revealed that short-chain PFBS (-11.84 Kcal/mol) and long-chain PFUnDA (-10.53 Kcal/mol) displayed the strongest binding interactions with human serum albumin protein. Lastly, research challenges and future perspectives for PFAS toxicological implications were also discussed, which helps to mitigate associated pollution and ecological risks.

Matched MeSH terms: Molecular Docking Simulation
Fulltext Pharmacotherapeutic Potential of Natural Products to Target the SARS-CoV-2 PLpro Using Molecular Screening and Simulation Approaches

Sayaf AM, Ahmad H, Aslam MA, Ghani SA, Bano S, Yousafi Q, et al.

Appl Biochem Biotechnol, 2023 Nov;195(11):6959-6978.
PMID: 36961512 DOI: 10.1007/s12010-023-04466-1

Because of the essential role of PLpro in the regulation of replication and dysregulation of the host immune sensing, it is considered a therapeutic target for novel drug development. To reduce the risk of immune evasion and vaccine effectiveness, small molecular therapeutics are the best complementary approach. Hence, we used a structure-based drug-designing approach to identify potential small molecular inhibitors for PLpro of SARS-CoV-2. Initial scoring and re-scoring of the best hits revealed that three compounds NPC320891 (2,2-Dihydroxyindene-1,3-Dione), NPC474594 (Isonarciclasine), and NPC474595 (7-Deoxyisonarciclasine) exhibit higher docking scores than the control GRL0617. Investigation of the binding modes revealed that alongside the essential contacts, i.e., Asp164, Glu167, Tyr264, and Gln269, these molecules also target Lys157 and Tyr268 residues in the active site. Moreover, molecular simulation demonstrated that the reported top hits also possess stable dynamics and structural packing. Furthermore, the residues' flexibility revealed that all the complexes demonstrated higher flexibility in the regions 120-140, 160-180, and 205-215. The 120-140 and 160-180 lie in the finger region of PLpro, which may open/close during the simulation to cover the active site and push the ligand inside. In addition, the total binding free energy was reported to be - 32.65 ± 0.17 kcal/mol for the GRL0617-PLpro, for the NPC320891-PLpro complex, the TBE was - 35.58 ± 0.14 kcal/mol, for the NPC474594-PLpro, the TBE was - 43.72 ± 0.22 kcal/mol, while for NPC474595-PLpro complex, the TBE was calculated to be - 41.61 ± 0.20 kcal/mol, respectively. Clustering of the protein's motion and FEL further revealed that in NPC474594 and NPC474595 complexes, the drug was seen to have moved inside the binding cavity along with the loop in the palm region harboring the catalytic triad, thus justifying the higher binding of these two molecules particularly. In conclusion, the overall results reflect favorable binding of the identified hits strongly than the control drug, thus demanding in vitro and in vivo validation for clinical purposes.

Matched MeSH terms: Molecular Docking Simulation
Fulltext Identification of Potential Biomarkers and Small Molecule Drugs for Bisphosphonate-Related Osteonecrosis of the Jaw (BRONJ): An Integrated Bioinformatics Study Using Big Data

Balachandran K, Ramli R, Karsani SA, Abdul Rahman M

Int J Mol Sci, 2023 May 11;24(10).
PMID: 37239981 DOI: 10.3390/ijms24108635

This study aimed to identify potential molecular mechanisms and therapeutic targets for bisphosphonate-related osteonecrosis of the jaw (BRONJ), a rare but serious side effect of bisphosphonate therapy. This study analyzed a microarray dataset (GSE7116) of multiple myeloma patients with BRONJ (n = 11) and controls (n = 10), and performed gene ontology, a pathway enrichment analysis, and a protein-protein interaction network analysis. A total of 1481 differentially expressed genes were identified, including 381 upregulated and 1100 downregulated genes, with enriched functions and pathways related to apoptosis, RNA splicing, signaling pathways, and lipid metabolism. Seven hub genes (FN1, TNF, JUN, STAT3, ACTB, GAPDH, and PTPRC) were also identified using the cytoHubba plugin in Cytoscape. This study further screened small-molecule drugs using CMap and verified the results using molecular docking methods. This study identified 3-(5-(4-(Cyclopentyloxy)-2-hydroxybenzoyl)-2-((3-hydroxybenzo[d]isoxazol-6-yl) methoxy) phenyl) propanoic acid as a potential drug treatment and prognostic marker for BRONJ. The findings of this study provide reliable molecular insight for biomarker validation and potential drug development for the screening, diagnosis, and treatment of BRONJ. Further research is needed to validate these findings and develop an effective biomarker for BRONJ.

Matched MeSH terms: Molecular Docking Simulation
Reverse vaccinology-based prediction of a multi-epitope SARS-CoV-2 vaccine and its tailoring to new coronavirus variants

Ezzemani W, Kettani A, Sappati S, Kondaka K, El Ossmani H, Tsukiyama-Kohara K, et al.

J Biomol Struct Dyn, 2023 Jul;41(11):4917-4938.
PMID: 35549819 DOI: 10.1080/07391102.2022.2075468

The genome feature of SARS-CoV-2 leads the virus to mutate and creates new variants of concern. Tackling viral mutations is also an important challenge for the development of a new vaccine. Accordingly, in the present study, we undertook to identify B- and T-cell epitopes with immunogenic potential for eliciting responses to SARS-CoV-2, using computational approaches and its tailoring to coronavirus variants. A total of 47 novel epitopes were identified as immunogenic triggering immune responses and no toxic after investigation with in silico tools. Furthermore, we found these peptide vaccine candidates showed a significant binding affinity for MHC I and MHC II alleles in molecular docking investigations. We consider them to be promising targets for developing peptide-based vaccines against SARS-CoV-2. Subsequently, we designed two efficient multi-epitopes vaccines against the SARS-CoV-2, the first one based on potent MHC class I and class II T-cell epitopes of S (FPNITNLCPF-NYNYLYRLFR-MFVFLVLLPLVSSQC), M (MWLSYFIASF-GLMWLSYFIASFRLF), E (LTALRLCAY-LLFLAFVVFLLVTLA), and N (SPRWYFYYL-AQFAPSASAFFGMSR). The second candidate is the result of the tailoring of the first designed vaccine according to three classes of SARS-CoV-2 variants. Molecular docking showed that the protein-protein binding interactions between the vaccines construct and TLR2-TLR4 immune receptors are stable complexes. These findings confirmed that the final multi-epitope vaccine could be easily adapted to new viral variants. Our study offers a shortlist of promising epitopes that can accelerate the development of an effective and safe vaccine against the virus and its adaptation to new variants.Communicated by Ramaswamy H. Sarma.

Matched MeSH terms: Molecular Docking Simulation
Fulltext A data-driven machine learning approach for discovering potent LasR inhibitors

Koh CMM, Ping LSY, Xuan CHH, Theng LB, San HS, Palombo EA, et al.

Bioengineered, 2023 Dec;14(1):2243416.
PMID: 37552115 DOI: 10.1080/21655979.2023.2243416

The rampant spread of multidrug-resistant Pseudomonas aeruginosa strains severely threatens global health. This severity is compounded against the backdrop of a stagnating antibiotics development pipeline. Moreover, with many promising therapeutics falling short of expectations in clinical trials, targeting the las quorum sensing (QS) system remains an attractive therapeutic strategy to combat P. aeruginosa infection. Thus, our primary goal was to develop a drug prediction algorithm using machine learning to identify potent LasR inhibitors. In this work, we demonstrated using a Multilayer Perceptron (MLP) algorithm boosted with AdaBoostM1 to discriminate between active and inactive LasR inhibitors. The optimal model performance was evaluated using 5-fold cross-validation and test sets. Our best model achieved a 90.7% accuracy in distinguishing active from inactive LasR inhibitors, an area under the Receiver Operating Characteristic Curve value of 0.95, and a Matthews correlation coefficient value of 0.81 when evaluated using test sets. Subsequently, we deployed the model against the Enamine database. The top-ranked compounds were further evaluated for their target engagement activity using molecular docking studies, Molecular Dynamics simulations, MM-GBSA analysis, and Free Energy Landscape analysis. Our data indicate that several of our chosen top hits showed better ligand-binding affinities than naringenin, a competitive LasR inhibitor. Among the six top hits, five of these compounds were predicted to be LasR inhibitors that could be used to treat P. aeruginosa-associated infections. To our knowledge, this study provides the first assessment of using an MLP-based QSAR model for discovering potent LasR inhibitors to attenuate P. aeruginosa infections.

Matched MeSH terms: Molecular Docking Simulation
Fulltext Profiling the Antidiabetic Potential of Compounds Identified from Fractionated Extracts of Entada africana toward Glucokinase Stimulation: Computational Insight

Onikanni SA, Lawal B, Munyembaraga V, Bakare OS, Taher M, Khotib J, et al.

Molecules, 2023 Jul 30;28(15).
PMID: 37570723 DOI: 10.3390/molecules28155752

Glucokinase plays an important role in regulating the blood glucose level and serves as an essential therapeutic target in type 2 diabetes management. Entada africana is a medicinal plant and highly rich source of bioactive ligands with the potency to develop new target drugs for glucokinase such as diabetes and obesity. Therefore, the study explored a computational approach to predict identified compounds from Entada africana following its intermolecular interactions with the allosteric binding site of the enzymes. We retrieved the three-dimensional (3D) crystal structure of glucokinase (PDB ID: 4L3Q) from the online protein data bank and prepared it using the Maestro 13.5, Schrödinger Suite 2022-3. The compounds identified were subjected to ADME, docking analysis, pharmacophore modeling, and molecular simulation. The results show the binding potential of the identified ligands to the amino acid residues, thereby suggesting an interaction of the amino acids with the ligand at the binding site of the glucokinase activator through conventional chemical bonds such as hydrogen bonds and hydrophobic interactions. The compatibility of the molecules was highly observed when compared with the standard ligand, thereby leading to structural and functional changes. Therefore, the bioactive components from Entada africana could be a good driver of glucokinase, thereby paving the way for the discovery of therapeutic drugs for the treatment of diabetes and its related complications.

Matched MeSH terms: Molecular Docking Simulation
Essential oil composition, anti-tyrosinase activity, and molecular docking studies of Knema intermedia Warb. (Myristicaceae)

Salihu AS, Salleh WMNHW, Setzer WN

Z Naturforsch C J Biosci, 2023 Jul 26;78(7-8):293-298.
PMID: 36960928 DOI: 10.1515/znc-2023-0003

Knema is one of the genera in the Myristicaceae family. The genus includes 60 species in Southeast Asia and is traditionally used for treating skin disorders. Here, for the first time, the essential oil, anti-tyrosinase, and molecular docking studies of Knema intermedia were evaluated. The essential oil was obtained by hydrodistillation and fully characterized by gas chromatography (GC-FID) and gas chromatography-mass spectrometry (GC-MS). Anti-tyrosinase activity was evaluated against mushroom tyrosinase, whereas molecular docking studies were performed using Autodock vina embedded in PyRx to evaluate the binding interactions of major components. A total of 37 components (97.3%) were successfully identified in the essential oil, which was characterized by high amounts of t-muurolol (20.1%), α-copaene (14.4%), δ-cadinene (13.9%), germacrene B (9.5%), and δ-selinene (7.0%). The essential oil displayed moderate inhibitory activity towards tyrosinase with an IC50 value of 70.2 μg/mL. The best docking energy was observed with δ-selinene (-7.8 kcal/mol), and it also forms interactions with His85, His263, and His244 which are important amino acid residues of the tyrosinase receptor. Hence, this study provides valuable scientific data on K. intermedia as potential candidate for the development of natural antiaging formulations.

Matched MeSH terms: Molecular Docking Simulation

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