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Computer-aided anti-cancer drug discovery of EGFR protein based on virtual screening of drug bank, ADMET, docking, DFT and molecular dynamic simulation studies

Roney M, Dubey A, Hassan Nasir M, Tufail A, Tajuddin SN, Mohd Aluwi MFF, et al.

J Biomol Struct Dyn, 2023 Sep 07.
PMID: 37676262 DOI: 10.1080/07391102.2023.2252092

Numerous malignancies, including breast cancer, non-small cell lung cancer, and chronic myeloid leukemia, are brought on by aberrant tyrosine kinase signaling. Since the current chemotherapeutic medicines are toxic, there is a great need and demand from cancer patients to find novel chemicals that are toxic-free or have low toxicity and that can kill tumor cells and stop their growth. This work describes the in-silico examination of substances from the drug bank as EGFR inhibitors. Firstly, drug-bank was screened using the pharmacophore technique to select the ligands and Erlotinib (DB00530) was used as matrix compound. The selected ligands were screened using ADMET and the hit compounds were subjected to docking. The lead compound from the docking was subjected to DFT and MD simulation study. Using the pharmacophore technique, 23 compounds were found through virtual drug bank screening. One hit molecule from the ADMET prediction was the subject of docking study. According to the findings, DB03365 molecule fits to the EGFR active site by several hydrogen bonding interactions with amino acids. Furthermore, DFT analysis revealed high reactivity for DB03365 compound in the binding pocket of the target protein, based on ELUMO, EHOMO and band energy gap. Furthermore, MD simulations for 100 ns revealed that the ligand interactions with the residues of EGFR protein were part of the essential residues for structural stability and functionality. However, DB03365 was a promising lead molecule that outperformed the reference compound in terms of performance and in-vitro and in-vivo experiments needs to validate the study.Communicated by Ramaswamy H. Sarma.
Fulltext ADME profiling, molecular docking, DFT, and MEP analysis reveal cissamaline, cissamanine, and cissamdine from Cissampelos capensis L.f. as potential anti-Alzheimer's agents

Alhawarri MB, Al-Thiabat MG, Dubey A, Tufail A, Fouad D, Alrimawi BH, et al.

RSC Adv, 2024 Mar 20;14(14):9878-9891.
PMID: 38528929 DOI: 10.1039/d4ra01070a

The current pharmacotherapies for Alzheimer's disease (AD) demonstrate limited efficacy and are associated with various side effects, highlighting the need for novel therapeutic agents. Natural products, particularly from medicinal plants, have emerged as a significant source of potential neuroprotective compounds. In this context, Cissampelos capensis L.f., renowned for its medicinal properties, has recently yielded three new proaporphine alkaloids; cissamaline, cissamanine, and cissamdine. Despite their promising bioactive profiles, the biological targets of these alkaloids in the context of AD have remained unexplored. This study undertakes a comprehensive in silico examination of the binding affinity and molecular interactions of these alkaloids with human protein targets implicated in AD. The drug likeness and ADME analyses indicate favorable pharmacokinetic profiles for these compounds, suggesting their potential efficacy in targeting the central nervous system. Molecular docking studies indicate that cissamaline, cissamanine, and cissamdine interact with key AD-associated proteins. These interactions are comparable to, or in some aspects slightly less potent than, those observed with established AD drugs, highlighting their potential as novel therapeutic agents for Alzheimer's disease. Crucially, Density Functional Theory (DFT) calculations offer deep insights into the electronic and energetic characteristics of these alkaloids. These calculations reveal distinct electronic properties, with differences in total energy, binding energy, HOMO-LUMO gaps, dipole moments, and electrophilicity indices. Such variations suggest unique reactivity profiles and molecular stability, pertinent to their pharmacological potential. Moreover, Molecular Electrostatic Potential (MEP) analyses provide visual representations of the electrostatic characteristics of these alkaloids. The analyses highlight areas prone to electrophilic and nucleophilic attacks, indicating their potential for specific biochemical interactions. This combination of DFT and MEP results elucidates the intricate electronic, energetic, and electrostatic properties of these compounds, underpinning their promise as AD therapeutic agents. The in silico findings of this study shed light on the promising potential of cissamaline, cissamanine, and cissamdine as agents for AD treatment. However, further in vitro and in vivo studies are necessary to validate these theoretical predictions and to understand the precise mechanisms through which these alkaloids may exert their therapeutic effects.
Computational evaluation of quinones of Nigella sativa L. as potential inhibitor of dengue virus NS5 methyltransferase

Roney M, Dubey A, Nasir MH, Huq AM, Tufail A, Tajuddin SN, et al.

J Biomol Struct Dyn, 2023 Aug 26.
PMID: 37632317 DOI: 10.1080/07391102.2023.2248262

Aedes aegypti is the primary vector for the transmission of the dengue virus, which causes dengue fever, dengue hemorrhagic illness and dengue shock syndrome. There is now no antiviral medication available to treat DENV, which kills thousands of people each year and infects millions of individuals. A possible target for the creation of fresh and efficient dengue treatments is the DENV-3 NS5 MTase. So, Nigella sativa quinones were examined using in silico methods to find natural anti-DENV compounds. The in silico docking was conducted utilising the Discovery Studio software on the quinones of N. sativa and the active site of the target protein DENV-3 NS5 MTase. In addition, the druggability and pharmacokinetics of the lead compound were assessed. Dithymoquinone was comparable to the reference compound in terms of its ability to bind to the active site of target protein. Dithymoquinone met the requirements for drug likeness and Lipinski's principles, as demonstrated by the ADMET analysis and drug likeness results. The current study indicated that the dithymoquinone from N. sativa had anti-DENV activity, suggesting further drug development and dengue treatment optimisation.Communicated by Ramaswamy H. Sarma.
Insights from in silico exploration of major curcumin analogs targeting human dipeptidyl peptidase IV

Roney M, Dubey A, Issahaku AR, Uddin MN, Tufail A, Wilhelm A, et al.

J Biomol Struct Dyn, 2024 Jan 23.
PMID: 38260948 DOI: 10.1080/07391102.2024.2306197

The goal of this work is to use a variety of in-silico techniques to identify anti-diabetic agents against DPP-IV enzyme from five main curcumin analogues. To produce the successful molecules, five main curcumin analogues were docked into the active site of DPP-IV enzyme. In comparison to the control molecule (Saxagliptin, -6.9 kcal/mol), all the compounds have the highest binding affinity (-7.6 to -7.7 kcal/mol) for the DPP-IV enzyme. These compounds underwent further testing for studies on drug-likeness, pharmacokinetics, and acute toxicity to see the efficacy and safety of compounds. To assess the stability of the docking complex and the binding posture identified during the docking experiment, our study got THC as the lead compound, which was then exposed to 200 ns of molecular dynamic simulation and PCA analysis. Additionally, DFT calculations were conducted to determine the thermodynamic, molecular orbital, and electrostatic potential characteristics of lead compound. Overall, the lead chemical has shown strong drug-like properties, is non-toxic, and has a sizable affinity for the DPP-IV enzyme.Communicated by Ramaswamy H. Sarma.
Pharmacophore-based virtual screening and in-silico study of natural products as potential DENV-2 RdRp inhibitors

Roney M, Huq AKMM, Issahaku AR, Soliman MES, Hossain MS, Mustafa AH, et al.

J Biomol Struct Dyn, 2023;41(21):12186-12203.
PMID: 36645141 DOI: 10.1080/07391102.2023.2166123

Dengue fever is a significant public health concern throughout the world, causing an estimated 500,000 hospitalizations and 20,000 deaths each year, despite the lack of effective therapies. The DENV-2 RdRp has been identified as a potential target for the development of new and effective dengue therapies. This research's primary objective was to discover an anti-DENV inhibitor using in silico ligand- and structure-based approaches. To begin, a ligand-based pharmacophore model was developed, and 130 distinct natural products (NPs) were screened. Docking of the pharmacophore-matched compounds were performed to the active site of DENV-2 RdRp protease . Eleven compounds were identified as potential DENV-2 RdRp inhibitors based on docking energy and binding interactions. ADMET and drug-likeness were done to predict their pharmacologic, pharmacokinetic, and drug-likeproperties . Compounds ranked highest in terms of pharmacokinetics and drug-like appearances were then subjected to additional toxicity testing to determine the leading compound. Additionally, MD simulation of the lead compound was performed to confirm the docked complex's stability and the binding site determined by docking. As a result, the lead compound (compound-108) demonstrated an excellent match to the pharmacophore, a strong binding contact and affinity for the RdRp enzyme, favourable pharmacokinetics, and drug-like characteristics. In summary, the lead compound identified in this study could be a possible DENV-2 RdRp inhibitor that may be further studied on in vitro and in vivo models to develop as a drug candidate.Communicated by Ramaswamy H. Sarma.
Fulltext Phenolic compounds of Theobroma cacao L. show potential against dengue RdRp protease enzyme inhibition by In-silico docking, DFT study, MD simulation and MMGBSA calculation

Huq AKMM, Roney M, Dubey A, Nasir MH, Tufail A, Aluwi MFFM, et al.

PLoS One, 2024;19(3):e0299238.
PMID: 38483871 DOI: 10.1371/journal.pone.0299238

BACKGROUND: Currently, there is no antiviral medication for dengue, a potentially fatal tropical infectious illness spread by two mosquito species, Aedes aegypti and Aedes albopictus. The RdRp protease of dengue virus is a potential therapeutic target. This study focused on the in silico drug discovery of RdRp protease inhibitors.
METHODS: To assess the potential inhibitory activity of 29 phenolic acids from Theobroma cacao L. against DENV3-NS5 RdRp, a range of computational methods were employed. These included docking, drug-likeness analysis, ADMET prediction, density functional theory (DFT) calculations, and molecular dynamics (MD) simulations. The aim of these studies was to confirm the stability of the ligand-protein complex and the binding pose identified during the docking experiment.
RESULTS: Twenty-one compounds were found to have possible inhibitory activities against DENV according to the docking data, and they had a binding affinity of ≥-37.417 kcal/mol for DENV3- enzyme as compared to the reference compound panduratin A. Additionally, the drug-likeness investigation produced four hit compounds that were subjected to ADMET screening to obtain the lead compound, catechin. Based on ELUMO, EHOMO, and band energy gap, the DFT calculations showed strong electronegetivity, favouravle global softness and chemical reactivity with considerable intra-molecular charge transfer between electron-donor to electron-acceptor groups for catechin. The MD simulation result also demonstrated favourable RMSD, RMSF, SASA and H-bonds in at the binding pocket of DENV3-NS5 RdRp for catechin as compared to panduratin A.
CONCLUSION: According to the present findings, catechin showed high binding affinity and sufficient drug-like properties with the appropriate ADMET profiles. Moreover, DFT and MD studies further supported the drug-like action of catechin as a potential therapeutic candidate. Therefore, further in vitro and in vivo research on cocoa and its phytochemical catechin should be taken into consideration to develop as a potential DENV inhibitor.
Fulltext Defining a Minimum Set of Standardized Patient-centered Outcome Measures for Macular Degeneration

Rodrigues IA, Sprinkhuizen SM, Barthelmes D, Blumenkranz M, Cheung G, Haller J, et al.

Am J Ophthalmol, 2016 08;168:1-12.
PMID: 27131774 DOI: 10.1016/j.ajo.2016.04.012

PURPOSE: To define a minimum set of outcome measures for tracking, comparing, and improving macular degeneration care.
DESIGN: Recommendations from a working group of international experts in macular degeneration outcomes registry development and patient advocates, facilitated by the International Consortium for Health Outcomes Measurement (ICHOM).
METHODS: Modified Delphi technique, supported by structured teleconferences, followed by online surveys to drive consensus decisions. Potential outcomes were identified through literature review of outcomes collected in existing registries and reported in major clinical trials. Outcomes were refined by the working group and selected based on impact on patients, relationship to good clinical care, and feasibility of measurement in routine clinical practice.
RESULTS: Standardized measurement of the following outcomes is recommended: visual functioning and quality of life (distance visual acuity, mobility and independence, emotional well-being, reading and accessing information); number of treatments; complications of treatment; and disease control. Proposed data collection sources include administrative data, clinical data during routine clinical visits, and patient-reported sources annually. Recording the following clinical characteristics is recommended to enable risk adjustment: age; sex; ethnicity; smoking status; baseline visual acuity in both eyes; type of macular degeneration; presence of geographic atrophy, subretinal fibrosis, or pigment epithelial detachment; previous macular degeneration treatment; ocular comorbidities.
CONCLUSIONS: The recommended minimum outcomes and pragmatic reporting standards should enable standardized, meaningful assessments and comparisons of macular degeneration treatment outcomes. Adoption could accelerate global improvements in standardized data gathering and reporting of patient-centered outcomes. This can facilitate informed decisions by patients and health care providers, plus allow long-term monitoring of aggregate data, ultimately improving understanding of disease progression and treatment responses.