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Kakoti BB, Zothantluanga JH, Deka K, Halder RK, Roy D. In silico design and computational screening of berberine derivatives for potential antidiabetic activity through allosteric activation of the AMPK pathway. In Silico Pharmacol 2025; 13:12. [PMID: 39780772 PMCID: PMC11704122 DOI: 10.1007/s40203-024-00295-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 12/09/2024] [Indexed: 01/11/2025] Open
Abstract
Globally, there is an increase in the prevalence of metabolic illnesses, including diabetes mellitus. However, current therapies for diabetes and other metabolic illnesses are not well understood. Pharmacological treatment of type 2 diabetes is challenging, moreover, the majority of antidiabetic medications are incompatible with individuals who have cardiac disease, renal illness, or liver damage. Despite the ongoing development of innovative medicines, the quest for an optimal treatment that serves both as a hypoglycaemic agent and mitigates diabetes-related problems remains unattained. Recent research demonstrates that berberine has significant promise in the treatment of diabetes. Berberine influences glucose metabolism by enhancing insulin secretion, promoting glycolysis, decreasing adipogenesis, disrupting the function of the mitochondria, stimulating the 5' adenosine monophosphate-activated protein kinase (AMPK) pathway, thereby augmenting glucokinase activity. In this study, we virtually designed and synthesized 5 berberine derivatives (data not yet published) to study their impact on the AMP-activated protein kinase (AMPK) pathway through molecular docking and dynamic simulation study. Activation of AMPK plays an important role by enhancing glucose uptake in cells. Berberine and its derivatives showed potential for allosteric activation of the AMPK pathway. The allosteric activation of AMPK α- & β-subunit involves complex interactions with standard activators like A-769662. Berberine and its derivatives showed potential binding affinity at the allosteric site of AMPK α- & β-subunit, forming similar interactions to A-769662. Molecular dynamic simulations indicated stability of these complexes. However, interactions of these derivatives with the AMPK γ-subunit were less stable, suggesting limited potential for allosteric activation at this site. Further studies are required to assess the long-term stability and efficacy of berberine and its derivatives as allosteric AMPK activators. Additionally, ADMET predictions suggest these derivatives to be safe, warranting further experimental and preclinical investigations as potential antidiabetic agents. Supplementary Information The online version contains supplementary material available at 10.1007/s40203-024-00295-0.
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Affiliation(s)
- Bibhuti Bhusan Kakoti
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam 786004 India
| | - James H. Zothantluanga
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam 786004 India
| | - Kangkan Deka
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam 786004 India
- NETES Institute of Pharmaceutical Science, NEMCARE Group of Institutions, Mirza, Kamrup, Guwahati, Assam 781125 India
| | - Raj Kumar Halder
- Ruhvenile Biomedical, Plot-8 OCF Pocket Institution, Sarita Vihar, Delhi, 110076 India
| | - Dhritiman Roy
- Department of Pharmaceutical Sciences, Dibrugarh University, Dibrugarh, Assam 786004 India
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Umar AK, Roy D, Abdalla M, Modafer Y, Al-Hoshani N, Yu H, Zothantluanga JH. In-silico screening of Acacia pennata and Bridelia retusa reveals pinocembrin-7-O-β-D-glucopyranoside as a promising β-lactamase inhibitor to combat antibiotic resistance. J Biomol Struct Dyn 2024; 42:8800-8812. [PMID: 37587843 DOI: 10.1080/07391102.2023.2248272] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2023] [Accepted: 08/08/2023] [Indexed: 08/18/2023]
Abstract
The β-lactamase of Pseudomonas aeruginosa is known to degrade β-lactam antibiotics such as penicillins, cephalosporins, monobactams, and carbapenems. With the discovery of an extended-spectrum β-lactamase in a clinical isolate of P. aeruginosa, the bacterium has become multi-drug resistant. In this study, we aim to identify new β-lactamase inhibitors by virtually screening a total of 43 phytocompounds from two Indian medicinal plants. In the molecular docking studies, pinocembrin-7-O-β-D-glucopyranoside (P7G) (-9.6 kcal/mol) from Acacia pennata and ellagic acid (EA) (-9.2 kcal/mol) from Bridelia retusa had lower binding energy than moxalactam (-8.4 kcal/mol). P7G and EA formed 5 (Ser62, Asn125, Asn163, Thr209, and Ser230) and 4 (Lys65, Ser123, Asn125, and Glu159) conventional hydrogens bonds with the active site residues. 100 ns MD simulations revealed that moxalactam and P7G (but not EA) were able to form a stable complex. The binding free energy calculations further revealed that P7G (-59.6526 kcal/mol) formed the most stable complex with β-lactamase when compared to moxalactam (-46.5669 kcal/mol) and EA (-28.4505 kcal/mol). The HOMO-LUMO and other DFT parameters support the stability and chemical reactivity of P7G at the active site of β-lactamase. P7G passed all the toxicity tests and bioavailability tests indicating that it possesses drug-likeness. Among the studied compounds, we identified P7G of A. pennata as the most promising phytocompound to combat antibiotic resistance by potentially inhibiting the β-lactamase of P. aeruginosa.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Abd Kakhar Umar
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Universitas Padjadjaran, Sumedang, Indonesia
| | - Dhritiman Roy
- Department of Pharmaceutical Sciences, Faculty of Science and Engineering, Dibrugarh University, Dibrugarh, Assam, India
| | - Mohnad Abdalla
- Pediatric Research Institute, Children's Hospital Affiliated to Shandong University, Jinan, China
| | - Yosra Modafer
- Department of Biology, Faculty of Science, Jazan University, Jazan, Saudi Arabia
| | - Nawal Al-Hoshani
- Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia
| | - Han Yu
- Pediatric Research Institute, Children's Hospital Affiliated to Shandong University, Jinan, China
- Department of Computational Biology, School of Life Sciences, Fudan University, Shanghai, China
| | - James H Zothantluanga
- Department of Pharmaceutical Sciences, Faculty of Science and Engineering, Dibrugarh University, Dibrugarh, Assam, India
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Ho WY, Shen ZH, Chen Y, Chen TH, Lu X, Fu YS. Therapeutic implications of quercetin and its derived-products in COVID-19 protection and prophylactic. Heliyon 2024; 10:e30080. [PMID: 38765079 PMCID: PMC11098804 DOI: 10.1016/j.heliyon.2024.e30080] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 04/18/2024] [Accepted: 04/18/2024] [Indexed: 05/21/2024] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel human coronavirus, which has triggered a global pandemic of the coronavirus infectious disease 2019 (COVID-19). Outbreaks of emerging infectious diseases continue to challenge human health worldwide. The virus conquers human cells through the angiotensin-converting enzyme 2 receptor-driven pathway by mostly targeting the human respiratory tract. Quercetin is a natural flavonoid widely represented in the plant kingdom. Cumulative evidence has demonstrated that quercetin and its derivatives have various pharmacological properties including anti-cancer, anti-hypertension, anti-hyperlipidemia, anti-hyperglycemia, anti-microbial, antiviral, neuroprotective, and cardio-protective effects, because it is a potential treatment for severe inflammation and acute respiratory distress syndrome. Furthermore, it is the main life-threatening condition in patients with COVID-19. This article provides a comprehensive review of the primary literature on the predictable effectiveness of quercetin and its derivatives docked to multi-target of SARS-CoV-2 and host cells via in silico and some of validation through in vitro, in vivo, and clinically to fight SARS-CoV-2 infections, contribute to the reduction of inflammation, which suggests the preventive and therapeutic latency of quercetin and its derived-products against COVID-19 pandemic, multisystem inflammatory syndromes (MIS), and long-COVID.
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Affiliation(s)
- Wan-Yi Ho
- Department of Anatomy, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Zi-Han Shen
- Department of Clinical Medicine, Xiamen Medical College, Xiamen, 361023, Fujian, China
| | - Yijing Chen
- Department of Dentisty, Xiamen Medical College, Xiamen, 361023, Fujian, China
| | - Ting-Hsu Chen
- Graduate Institute of Brain and Mind Sciences, College of Medicine, National Taiwan University, Taipei, 10051, Taiwan
| | - XiaoLin Lu
- Anatomy Section, Department of Basic Medical Science, Xiamen Medical College, Xiamen, 361023, Fujian, China
| | - Yaw-Syan Fu
- Institute of Respiratory Disease, Department of Basic Medical Science, Xiamen Medical College, Xiamen, 361023, Fujian, China
- Anatomy Section, Department of Basic Medical Science, Xiamen Medical College, Xiamen, 361023, Fujian, China
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Rajak P, Ganguly A. In silico study unfolds inhibitory potential of epicatechin gallate against SARS-CoV-2 entry and replication within the host cell. MECHANOBIOLOGY IN MEDICINE 2023; 1:100015. [PMID: 40395636 PMCID: PMC12082139 DOI: 10.1016/j.mbm.2023.100015] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 05/30/2023] [Accepted: 08/03/2023] [Indexed: 05/22/2025]
Abstract
Coronavirus disease-19 (COVID-19) is the ongoing pandemic affecting millions of people worldwide. Several vaccine candidates have been designed and developed for the causative virus, SARS-CoV-2. However high mutation rate in the viral genome and the emergence of new variants have challenged the effectiveness of these vaccines developed for previous strains. Hence, screening and identification of anti-SARS-CoV-2 agents having multi-target potency would be more impactful in the prevention of the disease. Epicatechin gallate (ECG) is a green tea polyphenol having various medicinal properties, including anti-oxidative and anti-inflammatory effects. However its role as anti-SARS-CoV-2 agent is not clear. Hence the present in silico study aims to investigate the binding potential of ECG with several proteins which are critical to SARS-CoV-2 entry and replication within the host cell. Molecular docking analyses have revealed that ECG could potentially block several amino acid residues of entry factors in host cells, spike protein, and many non-structural proteins through Hydrogen bonds and hydrophobic interactions. Such interactions with vital proteins could inhibit SARS-CoV-2 entry and its subsequent replication into the host. Therefore, ECG could be a potential therapeutic agent for the prevention of COVID-19. However, the findings of the present study demand further validation in animal models.
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Affiliation(s)
- Prem Rajak
- Department of Animal Science, Kazi Nazrul University, Asansol, West Bengal, India
| | - Abhratanu Ganguly
- Department of Animal Science, Kazi Nazrul University, Asansol, West Bengal, India
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Zothantluanga JH, Umar AK, Aswin K, Rajkhowa S, Chetia D. Revelation of potential drug targets of luteolin in Plasmodium falciparum through multi-target molecular dynamics simulation studies. J Biomol Struct Dyn 2023; 42:11612-11628. [PMID: 37776013 DOI: 10.1080/07391102.2023.2263875] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Accepted: 09/20/2023] [Indexed: 10/01/2023]
Abstract
In-silico techniques offer a fast, accurate, reliable, and economical approach to studying the molecular interactions between compounds and proteins. In this study, our main aim is to use in-silico techniques as a rational approach for the prediction of the molecular drug targets for luteolin against Plasmodium falciparum. Multi-target molecular docking, 100 nanoseconds (ns) molecular dynamics (MD) simulations, and Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) binding free energy calculations were carried out for luteolin against dihydrofolate reductase thymidylate synthase (PfDHFR-TS), dihydroorotate dehydrogenase (PfDHODH), and falcipain-2. The native ligands of each protein were used as a reference to evaluate the performance of luteolin. Luteolin outperformed the native ligands of all proteins at molecular docking and MD simulations studies. However, in the MM-GBSA calculations, luteolin outperformed the native ligand of only PfDHFR-TS but not PfDHODH and falcipain-2. Among the studied proteins, the in-silico approach predicted PfDHFR-TS as the most favorable drug target for luteolin.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- James H Zothantluanga
- Department of Pharmaceutical Sciences, Faculty of Science and Engineering, Dibrugarh University, Dibrugarh, India
| | - Abd Kakhar Umar
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Universitas Padjadjaran, Jatinangor, Indonesia
| | - Keerthic Aswin
- Council of Scientific and Industrial Research, Institute of Genomics and Integrative Biology, New Delhi, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India
| | - Sanchaita Rajkhowa
- Centre for Biotechnology and Bioinformatics, Faculty of Biological Sciences, Dibrugarh University, Dibrugarh, India
| | - Dipak Chetia
- Department of Pharmaceutical Sciences, Faculty of Science and Engineering, Dibrugarh University, Dibrugarh, India
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Kakhar Umar A, Zothantluanga JH, Luckanagul JA, Limpikirati P, Sriwidodo S. Structure-based computational screening of 470 natural quercetin derivatives for identification of SARS-CoV-2 M pro inhibitor. PeerJ 2023; 11:e14915. [PMID: 36935912 PMCID: PMC10022500 DOI: 10.7717/peerj.14915] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 01/26/2023] [Indexed: 03/16/2023] Open
Abstract
Coronavirus disease 2019 (COVID-19) is a global pandemic infecting the respiratory system through a notorious virus known as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Due to viral mutations and the risk of drug resistance, it is crucial to identify new molecules having potential prophylactic or therapeutic effect against SARS-CoV-2 infection. In the present study, we aimed to identify a potential inhibitor of SARS-CoV-2 through virtual screening of a compound library of 470 quercetin derivatives by targeting the main protease-Mpro (PDB ID: 6LU7). The study was carried out with computational techniques such as molecular docking simulation studies (MDSS), molecular dynamics (MD) simulations, and molecular mechanics generalized Born surface area (MMGBSA) techniques. Among the natural derivatives, compound 382 (PubChem CID 65604) showed the best binding affinity to Mpro (-11.1 kcal/mol). Compound 382 interacted with LYS5, TYR126, GLN127, LYS137, ASP289, PHE291, ARG131, SER139, GLU288, and GLU290 of the Mpro protein. The SARS-CoV-2 Mpro-382 complex showed acceptable stability during the 100 ns MD simulations. The SARS-CoV-2 Mpro-382 complex also showed an MM-GBSA binding free energy value of -54.0 kcal/mol. The binding affinity, stability, and free energy results for 382 and Mpro were better than those of the native ligand and the standard inhibitors ledipasvir and cobicistat. The conclusion of our study was that compound 382 has the potential to inhibit SARS-Cov-2 Mpro. However, further investigations such as in-vitro assays are recommended to confirm its in-silico potency.
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Affiliation(s)
- Abd. Kakhar Umar
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Padjadjaran University, Sumedang, Jawa barat, Indonesia
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Chulalongkorn University, Bangkok, Thailand
| | - James H. Zothantluanga
- Department of Pharmaceutical Sciences, Faculty of Pharmacy, Dibrugarh University, Assam, India
| | - Jittima Amie Luckanagul
- Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Chulalongkorn University, Bangkok, Thailand
| | - Patanachai Limpikirati
- Department of Food and Pharmaceutical Chemistry, Faculty of Pharmacy, Chulalongkorn University, Bangkok, Thailand
| | - Sriwidodo Sriwidodo
- Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Padjadjaran University, Sumedang, Jawa barat, Indonesia
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Ganguly A, Mandi M, Dutta A, Rajak P. In Silico Analysis Reveals the Inhibitory Potential of Madecassic Acid against Entry Factors of SARS-CoV-2. ACS APPLIED BIO MATERIALS 2023; 6:652-662. [PMID: 36608326 PMCID: PMC9844099 DOI: 10.1021/acsabm.2c00916] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Accepted: 12/28/2022] [Indexed: 01/07/2023]
Abstract
Coronavirus disease 19 (COVID-19) is the ongoing global health emergency caused by SARS-CoV-2 infection. The virus is highly contagious, affecting millions of people worldwide. SARS-CoV-2, with its trimeric spike glycoprotein, interacts with the angiotensin-converting enzyme 2 (ACE2) receptor and other co-receptors like basigin to invade the host cell. Moreover, certain host proteases like transmembrane serine proteases, furin, neuropilin 1 (NRP1), and endosomal cathepsins are involved in the priming of spike glycoproteins at the S1/S2 interface. This is critical for the entry of viral genome and its replication in the host cytoplasm. Vaccines and anti-SARS-CoV-2 drugs have been developed to overcome the infection. Nonetheless, the frequent emergence of mutant variants of the virus has imposed serious concerns regarding the efficacy of therapeutic agents, including vaccines that were developed for previous strains. Thus, screening and development of pharmaceutical agents with multi-target potency could be a better choice to restrain SARS-CoV-2 infection. Madecassic acid (MDCA) is a pentacyclic triterpenoid found in Centella asiatica. It has multiple medicinal properties like anti-oxidative, anti-inflammatory, and anti-diabetic potential. However, its implication as an anti- SARS-CoV-2 agent is still obscure. Hence, in the present in silico study, the binding affinities of MDCA for spike proteins, their receptors, and proteases were investigated. Results indicated that MDCA interacts with ligand-binding pockets of the spike receptor binding domain, ACE2, basigin, and host proteases, viz. transmembrane serine proteinase, furin, NRP1, and endosomal cathepsins, with greater affinities. Moreover, the MDCA-protein interface was strengthened by prominent hydrogen bonds and several hydrophobic interactions. Therefore, MDCA could be a promising multi-target therapeutic agent against SARS-CoV-2 infection.
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Affiliation(s)
- Abhratanu Ganguly
- Department of Animal Science, Kazi Nazrul
University, Paschim Bardhaman, West Bengal713340,
India
| | - Moutushi Mandi
- Department of Zoology, The University of
Burdwan, Purba Bardhaman, West Bengal713104,
India
| | - Anik Dutta
- Post Graduate Department of Zoology,
Darjeeling Government College, Darjeeling, West Bengal734104,
India
| | - Prem Rajak
- Department of Animal Science, Kazi Nazrul
University, Paschim Bardhaman, West Bengal713340,
India
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Zothantluanga JH, Umar AK, Lalhlenmawia H, Vinayagam S, Borthakur MS, Patowary L, Tayeng D. Computational screening of phytochemicals for anti-parasitic drug discovery. PHYTOCHEMISTRY, COMPUTATIONAL TOOLS AND DATABASES IN DRUG DISCOVERY 2023:257-283. [DOI: 10.1016/b978-0-323-90593-0.00005-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
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Dankwa B, Broni E, Enninful KS, Kwofie SK, Wilson MD. Consensus docking and MM-PBSA computations identify putative furin protease inhibitors for developing potential therapeutics against COVID-19. Struct Chem 2022; 33:2221-2241. [PMID: 36118173 PMCID: PMC9470509 DOI: 10.1007/s11224-022-02056-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 09/05/2022] [Indexed: 12/16/2022]
Abstract
The coronavirus disease 2019 (COVID-19) is a pandemic that has severely posed substantial health challenges and claimed millions of lives. Though vaccines have been produced to stem the spread of this disease, the death rate remains high since drugs used for treatment have therapeutic challenges. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes the disease, has a slew of potential therapeutic targets. Among them is the furin protease, which has a cleavage site on the virus’s spike protein. The cleavage site facilitates the entry of the virus into human cells via cell–cell fusion. This critical involvement of furin in the disease pathogenicity has made it a viable therapeutic strategy against the virus. This study employs the consensus docking approach using HYBRID and AutoDock Vina to virtually screen a pre-filtered library of 3942 natural product compounds of African origin against the human furin protease (PDB: 4RYD). Twenty of these compounds were selected as hits after meeting molecular docking cut-off of − 7 kcal.mol−1, pose alignment inspection, and having favorable furin-ligand interactions. An area under the curve (AUC) value of 0.72 was computed from the receiver operator characteristic (ROC) curve, and Boltzmann-enhanced discrimination of the ROC curve (BEDROC) value of 0.65 showed that AutoDock Vina was a reasonable tool for selecting actives for this target. Seven of these hits were proposed as potential leads having had bonding interactions with catalytic triad residues Ser368, His194, and Asp153, and other essential residues in the active site with plausible binding free energies between − 189 and − 95 kJ/mol from the Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations as well as favorable ADME/Tox properties. The molecules were also predicted as antiviral, anti-inflammatory, membrane permeability inhibitors, RNA synthesis inhibitors, cytoprotective, and hepatoprotective with probable activity (Pa) above 0.5 and probable inactivity values below 0.1. Some of them also have anti-influenza activity. Influenza virus has many similarities with SARS-CoV-2 in their mode of entry into human cells as both are facilitated by the furin protease. Pinobanksin 3-(E)-caffeate, one of the potential leads is a propolis compound. Propolis compounds have shown inhibitory effects against ACE2, TMPRSS2, and PAK1 signaling pathways of SARS-CoV-2 in previous studies. Likewise, quercitrin is structurally similar to isoquercetin, which is currently in clinical trials as possible medication for COVID-19.
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Affiliation(s)
- Bismark Dankwa
- Department of Parasitology, Noguchi Memorial Institute for Medical Research (NMIMR), College of Health Sciences (CHS), University of Ghana, Legon, Accra LG 581, Ghana
- Department of Computer Science, School of Physical & Mathematical Science, College of Basic & Applied Sciences, University of Ghana, LG 163 Legon, Accra Ghana
| | - Emmanuel Broni
- Department of Parasitology, Noguchi Memorial Institute for Medical Research (NMIMR), College of Health Sciences (CHS), University of Ghana, Legon, Accra LG 581, Ghana
- Department of Biomedical Engineering, School of Engineering Sciences, College of Basic & Applied Sciences, University of Ghana, Legon, Accra LG 77, Ghana
- Department of Medicine, Loyola University Medical Center, Maywood, IL 60153 USA
| | - Kweku S. Enninful
- Department of Parasitology, Noguchi Memorial Institute for Medical Research (NMIMR), College of Health Sciences (CHS), University of Ghana, Legon, Accra LG 581, Ghana
| | - Samuel K. Kwofie
- Department of Biomedical Engineering, School of Engineering Sciences, College of Basic & Applied Sciences, University of Ghana, Legon, Accra LG 77, Ghana
- Department of Biochemistry, Cell and Molecular Biology, West African Centre for Cell Biology of Infectious Pathogens, College of Basic and Applied Sciences, University of Ghana, Accra LG 54, Ghana
| | - Michael D. Wilson
- Department of Parasitology, Noguchi Memorial Institute for Medical Research (NMIMR), College of Health Sciences (CHS), University of Ghana, Legon, Accra LG 581, Ghana
- Department of Medicine, Loyola University Medical Center, Maywood, IL 60153 USA
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Antiviral phytocompounds “ellagic acid” and “(+)-sesamin” of Bridelia retusa identified as potential inhibitors of SARS-CoV-2 3CL pro using extensive molecular docking, molecular dynamics simulation studies, binding free energy calculations, and bioactivity prediction. Struct Chem 2022; 33:1445-1465. [PMID: 35571865 PMCID: PMC9086128 DOI: 10.1007/s11224-022-01959-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Accepted: 04/28/2022] [Indexed: 12/24/2022]
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected billions and has killed millions to date. Studies are being carried out to find therapeutic molecules that can potentially inhibit the replication of SARS-CoV-2. 3-chymotrypsin-like protease (3CL pro) involved in the polyprotein cleavage process is believed to be the key target for viral replication, and hence is an attractive target for the discovery of antiviral molecules. In the present study, we aimed to identify natural phytocompounds from Bridelia retusa as potential inhibitors of SARS-CoV-2 3CL pro (PDB ID: 6M2N) using in silico techniques. Molecular docking studies conducted with three different tools in triplicates revealed that ellagic acid (BR6) and (+)-sesamin (BR13) has better binding affinity than the co-crystal inhibitor “3WL” of 6M2N. BR6 and BR13 were found to have a high LD50 value with good bioavailability. 3WL, BR6, and BR13 bind to the same active binding site and interacted with the HIS41-CYS145 catalytic dyad including other crucial amino acids. Molecular dynamics simulation studies revealed stability of protein–ligand complexes as evidenced from root-mean-square deviations, root-mean-square fluctuations (RMSF), protein secondary structure elements, ligand-RMSF, protein–ligand contacts, ligand torsions, and ligand properties. BR6 (−22.3064 kcal/mol) and BR13 (−19.1274 kcal/mol) showed a low binding free energy value. The Bayesian statistical model revealed BR6 and BR13 as better protease inhibitors than 3WL. Moreover, BR6 and BR13 had already been reported to elicit antiviral activities. Therefore, we conclude that ellagic acid and (+)-sesamin as natural antiviral phytocompounds with inhibitory potential against SARS-CoV-2 3CL pro.
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Isolation, Identification, Spectral Studies and X-ray Crystal Structures of Two Compounds from Bixa orellana, DFT Calculations and DNA Binding Studies. CRYSTALS 2022. [DOI: 10.3390/cryst12030380] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
4,6-Diacetylresorcinol (1) and 3-O-methylellagic acid dihydrate (2), both biologically significant compounds, were extracted from Bixa orellana and studied using IR, 1H, and 13C NMR, and UV-vis spectroscopic techniques. X-ray crystallographic techniques were also used to establish the molecular structure of the isolated compounds 1 and 2. Geometric parameters, vibrational frequencies, and gauge including atomic orbital (GIAO) 1H and 13C NMR of 1 and 2 in the ground state were computed by the density functional theory (DFT) using B3LYP/6-311G(d,p) basis set backing up experimental studies and established the correct structure of isolated compounds. The parameters obtained from the combined DFT, and X-ray diffraction studies are mutually agreed to establish correct structures of 1 and 2. In addition, an electrostatic potential map and HOMO−LUMO energy gap were made using the DFT calculation to determine the distribution of energy and the chemical reactivity region of the isolated compounds. The current study also provides further insights into the interaction of compound 2 with ct-DNA using numerous biophysical and in silico techniques. Moreover, in silico studies indicate that compound 2 binds to the DNA in the minor groove. Lipinski’s rule of five revealed a higher tendency of compound 2 towards drug-likeness. The bioavailability and synthetic accessibility score for compound 2 was found to be 0.55 and 3.21, suggesting that compound 2 could serve as an effective therapeutic candidate.
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