Investigating Fungi-Derived Bioactive Molecules as Inhibitor of the SARS Coronavirus Papain Like Protease: Computational Based Study

Due to the rapid growth of the COVID-19 pandemic and its outcomes, developing a remedy to fight the predicament is critical. So far, it has infected more than 214,468,601 million people and caused the death of 4,470,969 million people according to the August 27, 2021, World Health Organization's (WHO) report. Several studies have been published on both computational and wet-lab approaches to develop antivirals for COVID-19, although there has been no success yet. However, the wet-lab approach is laborious, expensive, and time-consuming, and computational techniques have screened the activity of bioactive compounds from different sources with less effort and cost. For this investigation, we screened the binding affinity of fungi-derived bioactive molecules toward the SARS coronavirus papain-like protease (PLpro) by using computational approaches. Studies showed that protease inhibitors can be very effective in controlling virus-induced infections. Additionally, fungi represent a vast source of bioactive molecules, which could be potentially used for antiviral therapy. Fifty fungi-derived bioactive compounds were investigated concerning SARS-CoV-2 PLpro by using Auto Dock 4.2.1, Gromacs 2018. 2, ADMET, Swiss-ADME, FAF-Drugs 4.023, pKCSM, and UCLA-DOE server. From the list of the screened bioactive compounds, Dihydroaltersolanol C, Anthraquinone, Nigbeauvin A, and Catechin were selected with the Auto-Dock results of −8.68, −7.52, −10.46, and −10.58 Kcal/mol, respectively, based on their binding affinity compared to the reference drug. We presented the drug likeliness, toxicity, carcinogenicity, and mutagenicity of all compounds using ADMET analysis. They interacted with the amino acid residues, Gly163, Trp106, Ser111, Asp164, and Cys270, through hydrogen bonds. The root-mean-square deviation (RMSD), root-mean-square fluctuations (RMSF), solvent-accessible surface area (SASA), and radius of gyration (Rg) values revealed a stable interaction. From the overall analyses, we can conclude that Dihydroaltersolanol C, Anthraquinone, Nigbeauvin A, and Catechin are classified as promising candidates for PLpro, thus potentially useful in developing a medicine for COVID-19.

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Developing a model of the determinants of medication nonadherence in older community-dwelling patients

Annals of Behavioral Medicine ◽

10.1093/abm/kaz004 ◽

2019 ◽

Vol 53 (11) ◽

pp. 942-954 ◽

Cited By ~ 1

Author(s):

Affraic McLoughlin ◽

Kathleen Bennett ◽

Caitriona Cahir

Keyword(s):

Root Mean Square ◽

Direct Relationship ◽

Community Dwelling ◽

Mediating Effect ◽

World Health ◽

Mean Square ◽

Medication Nonadherence ◽

Related Factors ◽

Older Populations ◽

The Relationship

Abstract Medication nonadherence is associated with adverse health outcomes in older populations. The aim of this study was to develop a model that describes the relationship between the determinants of nonadherence, per the World Health Organization (WHO) model of nonadherence and the necessity–concerns framework (NCF) and nonadherence in a cohort of older community-dwelling patients. A retrospective cohort study of 855 community-dwelling patients aged ≥70 years from 15 practices. Medication nonadherence was assessed by (i) medication possession ratio (MPR < 80%) and (ii) the median MPR across all drugs dispensed. Patient questionnaires, interviews, and medical records measured the determinants of nonadherence per the WHO and NCF frameworks. Confirmatory factor analysis (CFA) was undertaken to generate the model of best fit. Two structural equation models (SEM) were developed to evaluate the relationship between the WHO factors, the NCF, and nonadherence (Model 1: MPR < 80%, Model 2: median MPR). The CFA produced a reasonable fit (χ2(113) = 203, p < .001; root mean square error of approximation = 0.03; comparative fit index = 0.98, and weighted root mean square residual = 0.97) and adequate internal consistency (r = .26–.40). SEM analysis (Model 1) showed a significant direct relationship between patient-related (β = 0.45, p < .01), socioeconomic (β = 0.20, p < .01), and therapy-related factors (β = −0.27, p < .01) and nonadherence (MPR < 80%). Similar results were found for Model 2 (median MPR). There was a significant direct relationship between medication concerns (β = −0.13, p < .01) and nonadherence. Therapy-related (β = −0.04, p < .05) and patient-related factors (β = −0.06, p < .05) also had a significant mediating effect on nonadherence through medication concerns. Health care professionals need to address medication concerns and management of adverse effects in older populations to improve adherence and clinical outcomes.

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Screening of Potent Phytochemical Inhibitors Against SARS-CoV-2 Main Protease: An Integrative Computational Approach

Frontiers in Bioinformatics ◽

10.3389/fbinf.2021.717141 ◽

2021 ◽

Vol 1 ◽

Author(s):

Shafi Mahmud ◽

Md. Robiul Hasan ◽

Suvro Biswas ◽

Gobindo Kumar Paul ◽

Shamima Afrose ◽

...

Keyword(s):

Root Mean Square ◽

Global Economy ◽

Transmission Rate ◽

Accessible Surface Area ◽

Dynamics Simulation ◽

Solvent Accessible Surface Area ◽

Radius Of Gyration ◽

Mean Square ◽

Protease Inhibition ◽

Main Protease

Coronavirus disease 2019 (COVID-19) is a potentially lethal and devastating disease that has quickly become a public health threat worldwide. Due to its high transmission rate, many countries were forced to implement lockdown protocols, wreaking havoc on the global economy and the medical crisis. The main protease (Mpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative virus for COVID-19, represent an effective target for the development of a new drug/vaccine because it is well-conserved and plays a vital role in viral replication. Mpro inhibition can stop the replication, transcription as well as recombination of SARS-CoV-2 after the infection and thus can halt the formation of virus particles, making Mpro a viable therapeutic target. Here, we constructed a phytochemical dataset based on a rigorous literature review and explored the probability that various phytochemicals will bind with the main protease using a molecular docking approach. The top three hit compounds, medicagol, faradiol, and flavanthrin, had binding scores of −8.3, −8.6, and −8.8 kcal/mol, respectively, in the docking analysis. These three compounds bind to the active groove, consisting of His41, Cys45, Met165, Met49, Gln189, Thr24, and Thr190, resulting in main protease inhibition. Moreover, the multiple descriptors from the molecular dynamics simulation, including the root-mean-square deviation, root-mean-square fluctuation, solvent-accessible surface area, radius of gyration, and hydrogen bond analysis, confirmed the stable nature of the docked complexes. In addition, absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis confirmed a lack of toxicity or carcinogenicity for the screened compounds. Our computational analysis may contribute toward the design of an effective drug against the main protease of SARS-CoV-2.

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Mollusc-Derived Brominated Indoles for the Selective Inhibition of Cyclooxygenase: A Computational Expedition

Molecules ◽

10.3390/molecules26216538 ◽

2021 ◽

Vol 26 (21) ◽

pp. 6538

Author(s):

Md. Mominur Rahman ◽

Md. Junaid ◽

S. M. Zahid Hosen ◽

Mohammad Mostafa ◽

Lei Liu ◽

...

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Molecular Dynamics Simulation ◽

Surface Area ◽

Root Mean Square ◽

Selective Inhibition ◽

Dynamics Simulation ◽

Solvent Accessible Surface Area ◽

Mean Square ◽

Cox 1

Inflammation plays an important role in different chronic diseases. Brominated indoles derived from the Australian marine mollusk Dicathais orbita (D. orbita) are of interest for their anti-inflammatory properties. This study evaluates the binding mechanism and potentiality of several brominated indoles (tyrindoxyl sulfate, tyrindoleninone, 6-bromoisatin, and 6,6′-dibromoindirubin) against inflammatory mediators cyclooxygenases-1/2 (COX-1/2) using molecular docking, followed by molecular dynamics simulation, along with physicochemical, drug-likeness, pharmacokinetic (pk), and toxicokinetic (tk) properties. Molecular docking identified that these indole compounds are anchored, with the main amino acid residues, positioned in the binding pocket of the COX-1/2, required for selective inhibition. Moreover, the molecular dynamics simulation based on root mean square deviation (RMSD), radius of gyration (Rg), solvent accessible surface area (SASA), and root mean square fluctuation (RMSF) analyses showed that these natural brominated molecules transit rapidly to a progressive constant configuration during binding with COX-1/2 and seem to accomplish a consistent dynamic behavior by maintaining conformational stability and compactness. The results were comparable to the Food and Drug Administration (FDA)-approved selective COX inhibitor, aspirin. Furthermore, the free energy of binding for the compounds assessed by molecular mechanics–Poisson–Boltzmann surface area (MM–PBSA) confirmed the binding capacity of indoles towards COX-1/2, with suitable binding energy values except for the polar precursor tyrindoxyl sulfate (with COX-1). The physicochemical and drug-likeness analysis showed zero violations of Lipinski’s rule, and the compounds are predicted to have excellent pharmacokinetic profiles. These indoles are projected to be non-mutagenic and free from hepatotoxicity, with no inhibition of human ether-a-go–go gene (hERG) I inhibitors, and the oral acute toxicity LD50 in rats is predicted to be similar or lower than aspirin. Overall, this work has identified a plausible mechanism for selective COX inhibition by natural marine indoles as potential therapeutic candidates for the mitigation of inflammation.

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Reappraisal of Trifluperidol against NSP-3 protein: Potential therapeutic for COVID-19

10.21203/rs.3.rs-52706/v1 ◽

2020 ◽

Author(s):

Ajita Pandey

Keyword(s):

Root Mean Square ◽

Dynamics Simulation ◽

Solvent Accessible Surface Area ◽

Radius Of Gyration ◽

Scoring Functions ◽

Mean Square ◽

Structural Protein ◽

Approved Drugs ◽

Fda Approved Drugs

Abstract Novel coronavirus disease 2019 (COVID-19) is a highly infectious disease that is caused by the recently discovered severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Because there are no specific vaccines or drugs for SARS-CoV-2, drug repurposing may be a promising approach. SARS-CoV-2 has a positive-sense RNA genome that encodes non-structural proteins (Nsps), which are essential for viral replication in the host cell. Non-structural protein 3 (Nsp3) is a multidomain protein and is the largest protein of the replicase complex. Nsp3 contains an ADP-ribose phosphatase (ADRP) domain, also called the macrodomain, which interferes with the host immune response. In the present study, we used computational regression methods to target the ADRP domain of Nsp3, using FDA-approved drugs. We virtually screened 2,892 FDA-approved drugs, using a combination of molecular docking and scoring functions. Saquinavir and trifluperidol were identified as potential leads and were further investigated using molecular dynamics simulation (MDS) to predict the stability and behavior of the ADRP-drug complexes. Analysis of root mean square deviation, root mean square fluctuation, radius of gyration, solvent accessible surface area and number of hydrogen bonds showed that the ADRP-trifluperidol complex is more stable than the ADRP-saquinavir complex. The screening and the MDS results suggest that trifluperidol is a novel inhibitor of the ADRP domain of Nsp3. Trifluperidol could, therefore, potentially be used to help control the spread of COVID-19, either alone or in combination with antiviral agents. Further in-vitro and in-vivo experiments are necessary to confirm our in silico results.

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Molecular Dynamics Study of Insulin Mutants

East European Journal of Physics ◽

10.26565/2312-4334-2021-2-15 ◽

2021 ◽

Keyword(s):

Molecular Dynamics ◽

Protein Structure ◽

Secondary Structure ◽

Root Mean Square ◽

Human Insulin ◽

Dynamics Simulation ◽

Solvent Accessible Surface Area ◽

Mean Square ◽

Wild Type ◽

Secondary Structure Content

Human insulin, a small protein hormone consisting of A-chain (21 residues) and B-chain (30 residues) linked by three disulfide bonds, is crucial for controlling the hyperglycemia in type I diabetes. In the present work molecular dynamics simulation (MD) with human insulin and its mutants was used to assess the influence of 10 point mutations (HisA8, ValA10, AspB10, GlnB17, AlaB17, GlnB18, AspB25, ThrB26, GluB27, AspB28), 6 double mutations (GluA13+GluB10, SerA13+GluB27, GluB1+GluB27, SerB2+AspB10, AspB9+GluB27, GluB16+GluB27) and one triple mutation (GluA15+AspA18+AspB3) in the protein sequence on the structure and dynamics of human insulin. A series of thermal unfolding MD simulations with wild type (WT) human insulin and its mutants was performed at 400 K with GROMACS software (version 5.1) using the CHARMM36m force field. The MD results have been analyzed in terms of the parameters characterizing both the global and local protein structure, such as the backbone root mean-square deviation, gyration radius, solvent accessible surface area, the root mean-square fluctuations and the secondary structure content. The MD simulation data showed that depending on time evolution of integral characteristics, the examined mutants can be tentatively divided into three groups: 1) the mutants HisA8, ValA10, AlaB17, AspB25, ThrB26, GluB27, GluA13+GluB10, GluB1+GluB27 and GluB16+GluB27, which exert stabilizing effect on the protein structure in comparison with wild type insulin; 2) the mutants GlnB17, AspB10, SerB2+AspB10 and GluA15+AspA18+AspB3 that did not significantly affect the dynamical properties of human insulin with a minimal stabilizing impact; 3) the mutants AspB28, AspB9+GluB27 and SerA13+GluB27, GlnB18, destabilizing the protein structure. Analysis of the secondary structure content provided evidence for the influence of AspB28, AspB9+GluB27 and SerA13+GluB27, GlnB18 on the insulin unfolding. Our MD results indicate that the replacement of superficial nonpolar residues in the insulin structure by hydrophilic ones gives rise to the increase in protein stability in comparison with the wild type protein.

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Unraveling the Deleterious Effects of Cancer-Driven STK11 Mutants through Conformational Sampling Approach

Cancer Informatics ◽

10.4137/cin.s38044 ◽

2016 ◽

Vol 15 ◽

pp. CIN.S38044 ◽

Cited By ~ 2

Author(s):

Merlin Lopus ◽

D. Meshach Paul ◽

R. Rajasekaran

Keyword(s):

Binding Energy ◽

Root Mean Square ◽

Critical Role ◽

Intramolecular Interactions ◽

Solvent Accessible Surface Area ◽

Driver Mutations ◽

Radius Of Gyration ◽

Conformational Sampling ◽

Mean Square ◽

Structural Variations

Tumor suppressor gene, STK11, encodes for serine-threonine kinase, which has a critical role in regulating cell growth and apoptosis. Mutations of the same lead to the inactivation of STK11, which eventually causes different types of cancer. In this study, we focused on identifying those driver mutations through analyzing structural variations of mutants, viz., D194N, E199K, L160P, and Y49D. Native and the mutants were analyzed to determine their geometrical deviations such as root-mean-square deviation, root-mean-square fluctuation, radius of gyration, potential energy, and solvent-accessible surface area using conformational sampling technique. Additionally, the global minimized structure of native and mutants was further analyzed to compute their intramolecular interactions and distribution of secondary structure. Subsequently, simulated thermal denaturation and docking studies were performed to determine their structural variations, which in turn alter the formation of active complex that comprises STK11, STRAD, and MO25. The deleterious effect of the mutants would result in a comparative loss of enzyme function due to variations in their binding energy pertaining to spatial conformation and flexibility. Hence, the structural variations in binding energy exhibited by the mutants, viz., D194N, E199K, L160P, and Y49D, to that of the native, consequently lead to pathogenesis.

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Plant-Based Phytochemical Screening by Targeting Main Protease of SARS-CoV-2 to Design Effective Potent Inhibitors

Biology ◽

10.3390/biology10070589 ◽

2021 ◽

Vol 10 (7) ◽

pp. 589

Author(s):

Shafi Mahmud ◽

Suvro Biswas ◽

Gobindo Kumar Paul ◽

Mohasana Akter Mita ◽

Maria Meha Promi ◽

...

Keyword(s):

Root Mean Square ◽

Active Sites ◽

Treatment Options ◽

Accessible Surface Area ◽

Solvent Accessible Surface Area ◽

Radius Of Gyration ◽

Mean Square ◽

Drug Candidates ◽

Main Protease ◽

Antibacterial And Antifungal

Currently, a worldwide pandemic has been declared in response to the spread of coronavirus disease 2019 (COVID-19), a fatal and fast-spreading viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The low availability of efficient vaccines and treatment options has resulted in a high mortality rate, bringing the world economy to its knees. Thus, mechanistic investigations of drugs capable of counteracting this disease are in high demand. The main protease (Mpro) expressed by SARS-CoV-2 has been targeted for the development of potential drug candidates due to the crucial role played by Mpro in viral replication and transcription. We generated a phytochemical library containing 1672 phytochemicals derived from 56 plants, which have been reported as having antiviral, antibacterial, and antifungal activity. A molecular docking program was used to screen the top three candidate compounds: epicatechin-3-O-gallate, psi-taraxasterol, and catechin gallate, which had respective binding affinities of −8.4, −8.5, and −8.8 kcal/mol. Several active sites in the targeted protein, including Cys145, His41, Met49, Glu66, and Met165, were found to interact with the top three candidate compounds. The multiple simulation profile, root-mean-square deviation, root-mean-square fluctuation, radius of gyration, and solvent-accessible surface area values supported the inflexible nature of the docked protein–compound complexes. The toxicity and carcinogenicity profiles were assessed, which showed that epicatechin-3-O-gallate, psi-taraxasterol, and catechin gallate had favorable pharmacological properties with no adverse effects. These findings suggest that these compounds could be developed as part of an effective drug development pathway to treat COVID-19.

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Efficacy of Phytochemicals Derived from Avicennia officinalis for the Management of COVID-19: A Combined In Silico and Biochemical Study

Molecules ◽

10.3390/molecules26082210 ◽

2021 ◽

Vol 26 (8) ◽

pp. 2210

Author(s):

Shafi Mahmud ◽

Gobindo Kumar Paul ◽

Mirola Afroze ◽

Shirmin Islam ◽

Swagota Briti Ray Gupt ◽

...

Keyword(s):

Root Mean Square ◽

Antioxidant Activities ◽

Binding Free Energy ◽

Healthcare Management ◽

Dynamics Simulation ◽

Solvent Accessible Surface Area ◽

Radius Of Gyration ◽

Mean Square ◽

Main Protease ◽

Avicennia Officinalis

The recent coronavirus disease 2019 (COVID-19) pandemic is a global threat for healthcare management and the economic system, and effective treatments against the pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus responsible for this disease have not yet progressed beyond the developmental phases. As drug refinement and vaccine progression require enormously broad investments of time, alternative strategies are urgently needed. In this study, we examined phytochemicals extracted from Avicennia officinalis and evaluated their potential effects against the main protease of SARS-CoV-2. The antioxidant activities of A. officinalis leaf and fruit extracts at 150 µg/mL were 95.97% and 92.48%, respectively. Furthermore, both extracts displayed low cytotoxicity levels against Artemia salina. The gas chromatography–mass spectroscopy analysis confirmed the identifies of 75 phytochemicals from both extracts, and four potent compounds, triacontane, hexacosane, methyl linoleate, and methyl palminoleate, had binding free energy values of −6.75, −6.7, −6.3, and −6.3 Kcal/mol, respectively, in complexes with the SARS-CoV-2 main protease. The active residues Cys145, Met165, Glu166, Gln189, and Arg188 in the main protease formed non-bonded interactions with the screened compounds. The root-mean-square difference (RMSD), root-mean-square fluctuations (RMSF), radius of gyration (Rg), solvent-accessible surface area (SASA), and hydrogen bond data from a molecular dynamics simulation study confirmed the docked complexes′ binding rigidity in the atomistic simulated environment. However, this study′s findings require in vitro and in vivo validation to ensure the possible inhibitory effects and pharmacological efficacy of the identified compounds.

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Heterocyclic Substitutions Greatly Improve Affinity and Stability of Folic Acid towards FRα. an In Silico Insight

Molecules ◽

10.3390/molecules26041079 ◽

2021 ◽

Vol 26 (4) ◽

pp. 1079

Author(s):

Mohammad G. Al-Thiabat ◽

Fadi G. Saqallah ◽

Amirah Mohd Gazzali ◽

Noratiqah Mohtar ◽

Beow Keat Yap ◽

...

Keyword(s):

Folic Acid ◽

Binding Affinity ◽

Root Mean Square ◽

Active Site ◽

Hydrophobic Interactions ◽

Md Simulations ◽

The Body ◽

Electrostatic Energy ◽

Epithelial Tissue ◽

Mean Square

Folate receptor alpha (FRα) is known as a biological marker for many cancers due to its overexpression in cancerous epithelial tissue. The folic acid (FA) binding affinity to the FRα active site provides a basis for designing more specific targets for FRα. Heterocyclic rings have been shown to interact with many receptors and are important to the metabolism and biological processes within the body. Nineteen FA analogs with substitution with various heterocyclic rings were designed to have higher affinity toward FRα. Molecular docking was used to study the binding affinity of designed analogs compared to FA, methotrexate (MTX), and pemetrexed (PTX). Out of 19 FA analogs, analogs with a tetrazole ring (FOL03) and benzothiophene ring (FOL08) showed the most negative binding energy and were able to interact with ASP81 and SER174 through hydrogen bonds and hydrophobic interactions with amino acids of the active site. Hence, 100 ns molecular dynamics (MD) simulations were carried out for FOL03, FOL08 compared to FA, MTX, and PTX. The root mean square deviation (RMSD) and root mean square fluctuation (RMSF) of FOL03 and FOL08 showed an apparent convergence similar to that of FA, and both of them entered the binding pocket (active site) from the pteridine part, while the glutamic part was stuck at the FRα pocket entrance during the MD simulations. Molecular mechanics Poisson-Boltzmann surface accessible (MM-PBSA) and H-bond analysis revealed that FOL03 and FOL08 created more negative free binding and electrostatic energy compared to FA and PTX, and both formed stronger H-bond interactions with ASP81 than FA with excellent H-bond profiles that led them to become bound tightly in the pocket. In addition, pocket volume calculations showed that the volumes of active site for FOL03 and FOL08 inside the FRα pocket were smaller than the FA–FRα system, indicating strong interactions between the protein active site residues with these new FA analogs compared to FA during the MD simulations.

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Molecular Dynamics Simulation of Cholera Toxin A-1 Polypeptide

Open Chemistry ◽

10.1515/chem-2016-0021 ◽

2016 ◽

Vol 14 (1) ◽

pp. 188-196 ◽

Cited By ~ 1

Author(s):

Syed Lal Badshah ◽

Abdul Naeem Khan ◽

Yahia Nasser Mabkhot

Keyword(s):

Molecular Dynamics ◽

Secondary Structure ◽

Cholera Toxin ◽

Root Mean Square ◽

Host Cells ◽

Dynamics Simulation ◽

Solvent Accessible Surface Area ◽

Radius Of Gyration ◽

Mean Square ◽

Toxin A

AbstractA molecular dynamics (MD) simulation study of the enzymatic portion of cholera toxin; cholera toxin A-1 polypeptide (CTA1) was performed at 283, 310 and 323 K. From total energy analysis it was observed that this toxin is stable thermodynamically and these outcomes were likewise confirmed by root mean square deviations (RMSD) investigations. The Cα root mean square fluctuation (RMSF) examinations revealed that there are a number of residues inside CTA1, which can be used as target for designing and synthesizing inhibitory drugs, in order to inactivate cholera toxin inside the human body. The fluctuations in the radius of gyration and hydrogen bonding in CTA1 proved that protein unfolding and refolding were normal routine phenomena in its structure at all temperatures. Solvent accessible surface area study identified the hydrophilic nature of the CTA1, and due to this property it can be a potential biological weapon. The structural identification (STRIDE) algorithm for proteins was successfully used to determine the partially disordered secondary structure of CTA1. On account of this partially disordered secondary structure, it can easily deceive the proteolytic enzymes of the endoplasmic reticulum of host cells.

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