Structure-Based Design, Docking and Binding Free Energy Calculations of A366 Derivatives as Spindlin1 Inhibitors

The chromatin reader protein Spindlin1 plays an important role in epigenetic regulation, through which it has been linked to several types of malignant tumors. In the current work, we report on the development of novel analogs of the previously published lead inhibitor A366. In an effort to improve the activity and explore the structure–activity relationship (SAR), a series of 21 derivatives was synthesized, tested in vitro, and investigated by means of molecular modeling tools. Docking studies and molecular dynamics (MD) simulations were performed to analyze and rationalize the structural differences responsible for the Spindlin1 activity. The analysis of MD simulations shed light on the important interactions. Our study highlighted the main structural features that are required for Spindlin1 inhibitory activity, which include a positively charged pyrrolidine moiety embedded into the aromatic cage connected via a propyloxy linker to the 2-aminoindole core. Of the latter, the amidine group anchor the compounds into the pocket through salt bridge interactions with Asp184. Different protocols were tested to identify a fast in silico method that could help to discriminate between active and inactive compounds within the A366 series. Rescoring the docking poses with MM-GBSA calculations was successful in this regard. Because A366 is known to be a G9a inhibitor, the most active developed Spindlin1 inhibitors were also tested over G9a and GLP to verify the selectivity profile of the A366 analogs. This resulted in the discovery of diverse selective compounds, among which 1s and 1t showed Spindlin1 activity in the nanomolar range and selectivity over G9a and GLP. Finally, future design hypotheses were suggested based on our findings.

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Microsecond-timescale MD simulation of EGFR minor mutation predicts the structural flexibility of EGFR kinase core that reflects EGFR inhibitor sensitivity

npj Precision Oncology ◽

10.1038/s41698-021-00170-7 ◽

2021 ◽

Vol 5 (1) ◽

Author(s):

Takahiro Yoshizawa ◽

Ken Uchibori ◽

Mitsugu Araki ◽

Shigeyuki Matsumoto ◽

Biao Ma ◽

...

Keyword(s):

Lung Cancer ◽

Kinase Inhibitors ◽

Binding Free Energy ◽

Salt Bridge ◽

Md Simulations ◽

Free Energy Calculations ◽

Egfr Mutations ◽

Analysis Strategy ◽

Egfr Tyrosine Kinase Inhibitors ◽

Future Drug

AbstractApproximately 15–30% of patients with lung cancer harbor mutations in the EGFR gene. Major EGFR mutations (>90% of EGFR-mutated lung cancer) are highly sensitive to EGFR tyrosine kinase inhibitors (TKIs). Many uncommon EGFR mutations have been identified, but little is known regarding their characteristics, activation, and sensitivity to various EGFR-TKIs, including allosteric inhibitors. We encountered a case harboring an EGFR-L747P mutation, originally misdiagnosed with EGFR-del19 mutation using a routine diagnostic EGFR mutation test, which was resistant to EGFR-TKI gefitinib. Using this minor mutation and common EGFR-activating mutations, we performed the binding free energy calculations and microsecond-timescale molecular dynamic (MD) simulations, revealing that the L747P mutation considerably stabilizes the active conformation through a salt-bridge formation between K745 and E762. We further revealed why several EGFR inhibitors, including the allosteric inhibitor, were ineffective. Our computational structural analysis strategy would be beneficial for future drug development targeting the EGFR minor mutations.

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Old Arsenal to Combat New Enemy: Repurposing of Commercially Available FDA Approved Drugs Against Main Protease of SARS-CoV2.

10.26434/chemrxiv.13032578 ◽

2020 ◽

Author(s):

Gagandeep Singh ◽

vishal srivastava ◽

Ritpratik Mishra ◽

Gaurav Goel ◽

Tapan Chaudhuri

Keyword(s):

Drug Design ◽

Binding Free Energy ◽

Md Simulations ◽

Docking Studies ◽

Free Energy Calculations ◽

World Health ◽

Main Protease ◽

Health Organization ◽

Approved Drugs ◽

Potential Inhibitors

In lack of vaccination and therapeutic drugs, the ongoing COVID-19 pandemic affected millions of people, causing 1,018,957 deaths worldwide (World health organization; 1st October 2020). The conventional drug design pipeline for effective and safer drug development is a costly and time-intensive affair. It takes around ten years in general from identifying a clinical candidate to get the approvals for actual applications. An effective way to cut short drug design pipeline in such emergency cases could be the repurposing of already approved drugs against novel targets. Here in this work, we explored the structure-based drug screening approach to find potential inhibitors of SARS-CoV2 main protease (Mpro) from the library of already FDA approved commercially available drugs. The site-specific and blind docking studies, in combination, suggest three potential inhibitors of Mpro, Ergotamine (ZINC000052955754), Nilotinib (ZINC000006716957) and Naldemedine (ZINC000100378061). Molecular dynamics (MD) simulations and binding free energy calculations using the MMPBSA method further reinforced the efficiency of the screened Mpro inhibitor candidates. The work yields enough evidence to conduct rigorous experimental validation of these drugs before utilizing them for the therapeutic management of SARS-CoV2 infection.

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Exploration of the structural requirements of Aurora Kinase B inhibitors by a combined QSAR, modelling and molecular simulation approach

Scientific Reports ◽

10.1038/s41598-021-97368-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Sajda Ashraf ◽

Kara E. Ranaghan ◽

Christopher J. Woods ◽

Adrian J. Mulholland ◽

Zaheer Ul-Haq

Keyword(s):

Binding Free Energy ◽

Pharmacophore Model ◽

3D Qsar ◽

Aurora Kinase ◽

Md Simulations ◽

Structural Features ◽

Free Energy Calculations ◽

Active Site Residues ◽

Qsar Analysis ◽

Aurora Kinase B

AbstractAurora kinase B plays an important role in the cell cycle to orchestrate the mitotic process. The amplification and overexpression of this kinase have been implicated in several human malignancies. Therefore, Aurora kinase B is a potential drug target for anticancer therapies. Here, we combine atom-based 3D-QSAR analysis and pharmacophore model generation to identify the principal structural features of acylureidoindolin derivatives that could potentially be responsible for the inhibition of Aurora kinase B. The selected CoMFA and CoMSIA model showed significant results with cross-validation values (q2) of 0.68, 0.641 and linear regression values (r2) of 0.971, 0.933 respectively. These values support the statistical reliability of our model. A pharmacophore model was also generated, incorporating features of reported crystal complex structures of Aurora kinase B. The pharmacophore model was used to screen commercial databases to retrieve potential lead candidates. The resulting hits were analyzed at each stage for diversity based on the pharmacophore model, followed by molecular docking and filtering based on their interaction with active site residues and 3D-QSAR predictions. Subsequently, MD simulations and binding free energy calculations were performed to test the predictions and to characterize interactions at the molecular level. The results suggested that the identified compounds retained the interactions with binding residues. Binding energy decomposition identified residues Glu155, Trp156 and Ala157 of site B and Leu83 and Leu207 of site C as major contributors to binding affinity, complementary to 3D-QSAR results. To best of our knowledge, this is the first comparison of WaterSwap field and 3D-QSAR maps. Overall, this integrated strategy provides a basis for the development of new and potential AK-B inhibitors and is applicable to other protein targets.

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Old Arsenal to Combat New Enemy: Repurposing of Commercially Available FDA Approved Drugs Against Main Protease of SARS-CoV2.

10.26434/chemrxiv.13032578.v1 ◽

2020 ◽

Author(s):

Gagandeep Singh ◽

vishal srivastava ◽

Ritpratik Mishra ◽

Gaurav Goel ◽

Tapan Chaudhuri

Keyword(s):

Drug Design ◽

Binding Free Energy ◽

Md Simulations ◽

Docking Studies ◽

Free Energy Calculations ◽

World Health ◽

Main Protease ◽

Health Organization ◽

Approved Drugs ◽

Potential Inhibitors

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Synthesis, Structural Characterization, and In Vitro and In Silico Antifungal Evaluation of Azo-Azomethine Pyrazoles (PhN2(PhOH)CHN(C3N2(CH3)3)PhR, R = H or NO2)

Molecules ◽

10.3390/molecules26247435 ◽

2021 ◽

Vol 26 (24) ◽

pp. 7435

Author(s):

Dorancelly Fernandez ◽

Andrés Restrepo-Acevedo ◽

Cristian Rocha-Roa ◽

Ronan Le Lagadec ◽

Rodrigo Abonia ◽

...

Keyword(s):

Molecular Docking ◽

Antifungal Activity ◽

Active Sites ◽

Antitumor Agents ◽

Binding Free Energy ◽

Building Blocks ◽

Docking Studies ◽

Free Energy Calculations ◽

Dynamics Simulations

The azo-azomethine imines, R1-N=N-R2-CH=N-R3, are a class of active pharmacological ligands that have been prominent antifungal, antibacterial, and antitumor agents. In this study, four new azo-azomethines, R1 = Ph, R2 = phenol, and R3 = pyrazol-Ph-R’ (R = H or NO2), have been synthesized, structurally characterized using X-ray, IR, NMR and UV–Vis techniques, and their antifungal activity evaluated against certified strains of Candida albicans and Cryptococcus neoformans. The antifungal tests revealed a high to moderate inhibitory activity towards both strains, which is regulated as a function of both the presence and the location of the nitro group in the aromatic ring of the series. These biological assays were further complemented with molecular docking studies against three different molecular targets from each fungus strain. Molecular dynamics simulations and binding free energy calculations were performed on the two best molecular docking results for each fungus strain. Better affinity for active sites for nitro compounds at the “meta” and “para” positions was found, making them promising building blocks for the development of new Schiff bases with high antifungal activity.

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Advances in the Treatment of Explicit Water Molecules in Docking and Binding Free Energy Calculations

Current Medicinal Chemistry ◽

10.2174/0929867325666180514110824 ◽

2020 ◽

Vol 26 (42) ◽

pp. 7598-7622 ◽

Cited By ~ 2

Author(s):

Xiao Hu ◽

Irene Maffucci ◽

Alessandro Contini

Keyword(s):

Drug Discovery ◽

Binding Free Energy ◽

Docking Studies ◽

Free Energy Calculations ◽

Binding Energies ◽

New Drugs ◽

Water Molecules ◽

Open Questions ◽

Dynamics Simulations ◽

Computational Drug Discovery

Background: The inclusion of direct effects mediated by water during the ligandreceptor recognition is a hot-topic of modern computational chemistry applied to drug discovery and development. Docking or virtual screening with explicit hydration is still debatable, despite the successful cases that have been presented in the last years. Indeed, how to select the water molecules that will be included in the docking process or how the included waters should be treated remain open questions. Objective: In this review, we will discuss some of the most recent methods that can be used in computational drug discovery and drug development when the effect of a single water, or of a small network of interacting waters, needs to be explicitly considered. Results: Here, we analyse the software to aid the selection, or to predict the position, of water molecules that are going to be explicitly considered in later docking studies. We also present software and protocols able to efficiently treat flexible water molecules during docking, including examples of applications. Finally, we discuss methods based on molecular dynamics simulations that can be used to integrate docking studies or to reliably and efficiently compute binding energies of ligands in presence of interfacial or bridging water molecules. Conclusions: Software applications aiding the design of new drugs that exploit water molecules, either as displaceable residues or as bridges to the receptor, are constantly being developed. Although further validation is needed, workflows that explicitly consider water will probably become a standard for computational drug discovery soon.

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High Throughput in Silico Identification of Novel Phytochemical Inhibitors for the Master Regulator of Inflammation (TNFα)

10.26434/chemrxiv.14178212.v2 ◽

2021 ◽

Author(s):

Pratap Kumar Parida ◽

Dipak Paul ◽

Debamitra Chakravorty

Keyword(s):

Small Molecule ◽

High Throughput ◽

In Silico ◽

Small Molecule Inhibitors ◽

Binding Free Energy ◽

Natural Compounds ◽

Free Energy Calculations ◽

Compound Libraries ◽

Relative Binding

<a>The over expression of Tumor necrosis factor-α (TNFα) has been implicated in a variety of disease and is classified as a therapeutic target for inflammatory diseases (Crohn disease, psoriasis, psoriatic arthritis, rheumatoid arthritis).Commercially available therapeutics are biologics which are associated with several risks and limitations. Small molecule inhibitors and natural compounds (saponins) were identified by researchers as lead molecules against TNFα, however, </a>they were often associated with high IC50 values which can lead to their failure in clinical trials. This warrants research related to identification of better small molecule inhibitors by screening of large compound libraries. Recent developments have demonstrated power of natural compounds as safe therapeutics, hence, in this work, we have identified TNFα phytochemical inhibitors using high throughput in silico screening approaches of 6000 phytochemicals followed by 200 ns molecular dynamics simulations and relative binding free energy calculations. The work yielded potent hits that bind to TNFα at its dimer interface. The mechanism targeted was inhibition of oligomerization of TNFα upon phytochemical binding to restrict its interaction with TNF-R1 receptor. MD simulation analysis resulted in identification of two phytochemicals that showed stable protein-ligand conformations over time. The two compounds were triterpenoids: Momordicilin and Nimbolin A with relative binding energy- calculated by MM/PBSA to be -190.5 kJ/Mol and -188.03 kJ/Mol respectively. Therefore, through this work it is being suggested that these phytochemicals can be used for further in vitro analysis to confirm their inhibitory action against TNFα or can be used as scaffolds to arrive at better drug candidates.

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Synthesis and Evaluation of 3-(1,3-dioxoisoindolin-2-yl)-N-substituted Phenyl Benzamide Analogues as HIV Integrase Strand Transfer Inhibitors

Anti-Infective Agents ◽

10.2174/2211352516666181102121920 ◽

2019 ◽

Vol 17 (2) ◽

pp. 105-114

Author(s):

Pankaj Wadhwa ◽

Priti Jain ◽

Arpit Patel ◽

Shantanu Shinde ◽

Hemant R. Jadhav

Keyword(s):

Structural Features ◽

Docking Studies ◽

Significant Inhibition ◽

Strand Transfer ◽

Hiv Integrase ◽

In Silico Docking ◽

Immunodeficiency Virus ◽

Hiv 1

Background: A series of novel 3-(1,3-dioxoisoindolin-2-yl)-N-substituted phenyl benzamide derivatives was synthesized and tested in vitro against human immunodeficiency virus type-1 Integrase (HIV-1 IN). Methods: Out of the 18 analogues, six (compounds 16c, 16h, 16i, 16m, 16n and 16r) showed significant inhibition of strand transfer by HIV-1 integrase. For these six compounds. IC50 was below 5.0 µM. In silico docking studies revealed that the presence of 2-phenyl isoindoline-1,3-dione motif was essential as it was found to interact with active site magnesium. Results: To further confirm the results, cell-based HIV-1 and HIV-2 inhibitory assay was carried out. Conclusion: These compounds possess structural features not seen in previously reported HIV-1 integrase inhibitors and thus can help further optimization of anti-HIV-1 integrase activity.

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Quinazolin-4-one derivatives lacking toxicity-producing attributes as glucokinase activators: design, synthesis, molecular docking, and in-silico ADMET prediction

Future Journal of Pharmaceutical Sciences ◽

10.1186/s43094-019-0012-y ◽

2019 ◽

Vol 5 (1) ◽

Cited By ~ 2

Author(s):

Saurabh C. Khadse ◽

Nikhil D. Amnerkar ◽

Manasi U. Dave ◽

Deepak K. Lokwani ◽

Ravindra R. Patil ◽

...

Keyword(s):

Molecular Docking ◽

In Silico ◽

Enzyme Assay ◽

Binding Free Energy ◽

Docking Studies ◽

Oral Glucose ◽

Substitution Pattern ◽

Glucokinase Activators ◽

In Silico Admet

Abstract Background A small library of quinazolin-4-one clubbed thiazole acetates/acetamides lacking toxicity-producing functionalities was designed, synthesized, and evaluated for antidiabetic potential as glucokinase activators (GKA). Molecular docking studies were done in the allosteric site of the human glucokinase (PDB ID: 1V4S) enzyme to assess the binding mode and interactions of synthesized hits for best-fit conformations. All the compounds were evaluated by in vitro enzymatic assay for GK activation. Results Data showed that compounds 3 (EC50 = 632 nM) and 4 (EC50 = 516 nM) showed maximum GK activation compared to the standards RO-281675 and piragliatin. Based on the results of the in vitro enzyme assay, docking studies, and substitution pattern, selected compounds were tested for their glucose-lowering effect in vivo by oral glucose tolerance test (OGTT) in normal rats. Compounds 3 (133 mg/dL) and 4 (135 mg/dL) exhibited prominent activity by lowering the glucose level to almost normal, eliciting the results in parallel to enzyme assay and docking studies. Binding free energy, hydrogen bonding, and π–π interactions of most active quinazolin-4-one derivatives 3 and 4 with key amino acid residues of the 1V4S enzyme were studied precisely. Preliminary in-silico absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction was carried out using SwissADME and PreADMET online software which revealed that all the compounds have the potential to become orally active antidiabetic agents as they obeyed Lipinski's rule of five. Conclusion The results revealed that the designed lead could be significant for the strategic design of safe, effective, and orally bioavailable quinazolinone derivatives as glucokinase activators.

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Sulfonanilide Derivatives in Identifying Novel Aromatase Inhibitors by Applying Docking, Virtual Screening, and MD Simulations Studies

BioMed Research International ◽

10.1155/2017/2105610 ◽

2017 ◽

Vol 2017 ◽

pp. 1-17 ◽

Cited By ~ 11

Author(s):

Shailima Rampogu ◽

Minky Son ◽

Chanin Park ◽

Hyong-Ha Kim ◽

Jung-Keun Suh ◽

...

Keyword(s):

Aromatase Inhibitors ◽

Causes Of Death ◽

Binding Free Energy ◽

Chemical Compounds ◽

Md Simulations ◽

Free Energy Calculations ◽

Lipinski’S Rule ◽

Discovery Studio ◽

Drug Candidates ◽

Lipinski’S Rule Of Five

Breast cancer is one of the leading causes of death noticed in women across the world. Of late the most successful treatments rendered are the use of aromatase inhibitors (AIs). In the current study, a two-way approach for the identification of novel leads has been adapted. 81 chemical compounds were assessed to understand their potentiality against aromatase along with the four known drugs. Docking was performed employing the CDOCKER protocol available on the Discovery Studio (DS v4.5). Exemestane has displayed a higher dock score among the known drug candidates and is labeled as reference. Out of 81 ligands 14 have exhibited higher dock scores than the reference. In the second approach, these 14 compounds were utilized for the generation of the pharmacophore. The validated four-featured pharmacophore was then allowed to screen Chembridge database and the potential Hits were obtained after subjecting them to Lipinski’s rule of five and the ADMET properties. Subsequently, the acquired 3,050 Hits were escalated to molecular docking utilizing GOLD v5.0. Finally, the obtained Hits were consequently represented to be ideal lead candidates that were escalated to the MD simulations and binding free energy calculations. Additionally, the gene-disease association was performed to delineate the associated disease caused by CYP19A1.

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