Molecular Dynamics-Derived Pharmacophore Model Explaining the Nonselective Aspect of KV10.1 Pore Blockers

The KV10.1 voltage-gated potassium channel is highly expressed in 70% of tumors, and thus represents a promising target for anticancer drug discovery. However, only a few ligands are known to inhibit KV10.1, and almost all also inhibit the very similar cardiac hERG channel, which can lead to undesirable side-effects. In the absence of the structure of the KV10.1–inhibitor complex, there remains the need for new strategies to identify selective KV10.1 inhibitors and to understand the binding modes of the known KV10.1 inhibitors. To investigate these binding modes in the central cavity of KV10.1, a unique approach was used that allows derivation and analysis of ligand–protein interactions from molecular dynamics trajectories through pharmacophore modeling. The final molecular dynamics-derived structure-based pharmacophore model for the simulated KV10.1–ligand complexes describes the necessary pharmacophore features for KV10.1 inhibition and is highly similar to the previously reported ligand-based hERG pharmacophore model used to explain the nonselectivity of KV10.1 pore blockers. Moreover, analysis of the molecular dynamics trajectories revealed disruption of the π–π network of aromatic residues F359, Y464, and F468 of KV10.1, which has been reported to be important for binding of various ligands for both KV10.1 and hERG channels. These data indicate that targeting the KV10.1 channel pore is also likely to result in undesired hERG inhibition, and other potential binding sites should be explored to develop true KV10.1-selective inhibitors as new anticancer agents.

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Exploration of Novel Xanthine Oxidase Inhibitors Based on 1,6-Dihydropyrimidine-5-Carboxylic Acids by an Integrated in Silico Study

International Journal of Molecular Sciences ◽

10.3390/ijms22158122 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8122

Author(s):

Na Zhai ◽

Chenchen Wang ◽

Fengshou Wu ◽

Liwei Xiong ◽

Xiaogang Luo ◽

...

Keyword(s):

Xanthine Oxidase ◽

Carboxylic Acids ◽

Hydrophobic Interactions ◽

Pharmacophore Model ◽

3D Qsar ◽

Md Simulations ◽

Pharmacophore Modeling ◽

Binding Modes ◽

Comfa Model ◽

Validation Parameters

Xanthine oxidase (XO) is an important target for the effective treatment of hyperuricemia-associated diseases. A series of novel 2-substituted 6-oxo-1,6-dihydropyrimidine-5-carboxylic acids (ODCs) as XO inhibitors (XOIs) with remarkable activities have been reported recently. To better understand the key pharmacological characteristics of these XOIs and explore more hit compounds, in the present study, the three-dimensional quantitative structure–activity relationship (3D-QSAR), molecular docking, pharmacophore modeling, and molecular dynamics (MD) studies were performed on 46 ODCs. The constructed 3D-QSAR models exhibited reliable predictability with satisfactory validation parameters, including q2 = 0.897, R2 = 0.983, rpred2 = 0.948 in a CoMFA model, and q2 = 0.922, R2 = 0.990, rpred2 = 0.840 in a CoMSIA model. Docking and MD simulations further gave insights into the binding modes of these ODCs with the XO protein. The results indicated that key residues Glu802, Arg880, Asn768, Thr1010, Phe914, and Phe1009 could interact with ODCs by hydrogen bonds, π-π stackings, or hydrophobic interactions, which might be significant for the activity of these XOIs. Four potential hits were virtually screened out using the constructed pharmacophore model in combination with molecular dockings and ADME predictions. The four hits were also found to be relatively stable in the binding pocket by MD simulations. The results in this study might provide effective information for the design and development of novel XOIs.

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ENERGY-BASED PHARMACOPHORE MODELING, VIRTUAL SCREENING, AND MOLECULAR DYNAMICS TO IDENTIFY POTENTIAL INHIBITORS FOR GLYCOGEN SYNTHASE KINASE 3 BETA

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2018.v11i2.22962 ◽

2018 ◽

Vol 11 (2) ◽

pp. 181

Author(s):

Sheema Jb ◽

Waheeta Hopper

Keyword(s):

Molecular Dynamics ◽

Wound Healing ◽

Glycogen Synthase ◽

Pharmacophore Model ◽

Pharmacophore Modeling ◽

Glycogen Synthase Kinase ◽

Glycogen Synthase Kinase 3 ◽

Systemic Side Effects ◽

The Stability ◽

Potential Inhibitors

Objective: Glycogen synthase kinase 3 beta (GSK3β) is one of the main targets for wound healing activity. Our objective is to identify novel inhibitors for GSK3β using in silico approach.Methods: Grid-based molecular docking, energy-based pharmacophore (e-pharmacophore) modeling, and molecular dynamics (MD) studies were performed for phytocompounds with GSK3β and compared with standard drugs using Schrodinger software.Results: The glide scores and the molecular interactions of the phytocompounds were well comparable to the standard drugs. The MD was performed for the target bound to the best scoring ligand, entagenic acid. The pharmacophore features of this docked complex were modeled as e-pharmacophore. The constructed e-pharmacophore model was screened against phytocompounds retrieved from literature to identify the ligands with similar pharmacophore features.Conclusion: The glide scores of fukinolic acid, cimicifugic acid, and linarin were −10.99, −8.28, and −7.25 kcal/mol, respectively. The further 50 nanoseconds MD study determined the stability of GSK3β-linarin complex. Nitrofurazone and sulfathiazole drugs can lead to systemic side effects. Hence, it is concluded that linarin could be a potent wound healing compound against GSK3β.

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Discovery of potential negative allosteric modulators of mGluR5 from natural products using pharmacophore modeling, molecular docking, and molecular dynamics simulation studies

Canadian Journal of Chemistry ◽

10.1139/cjc-2015-0197 ◽

2015 ◽

Vol 93 (11) ◽

pp. 1199-1206 ◽

Cited By ~ 5

Author(s):

Ludi Jiang ◽

Yong Li ◽

Liansheng Qiao ◽

Xi Chen ◽

Yusu He ◽

...

Keyword(s):

Molecular Dynamics ◽

Natural Products ◽

Molecular Docking ◽

Molecular Dynamics Simulation ◽

Pharmacophore Model ◽

Pharmacophore Modeling ◽

Dynamics Simulation ◽

Allosteric Modulators ◽

Subtype Selectivity ◽

Wide Range

mGluR5, which belongs to the G-protein-coupled receptor superfamily, is believed to be associated with many human diseases, such as a wide range of neurological disorders, gastroesophageal reflux disease, and cancer. Comparing with compounds that target on the orthosteric binding site, significant roles have been established for mGluR5 negative allosteric modulators (NAMs) due to their higher subtype selectivity and more suitable pharmacokinetic profiles. Nevertheless, to date, none of them have come to market for various reasons. In this study, a 3D quantitative pharmacophore model was generated by using the HypoGen module in Discovery Studio 4.0. With several validation methods ultilized, the optimal pharmacophore model Hypo2 was selected to discover potential mGluR5 NAMs from natural products. Two hundred and seventeen potential NAMs were obtained after being filtered by Lipinski’s rule (≥4). Then, molecular docking was used to refine the pharmacophore-based screening results and analyze the binding mode of NAMs and mGluR5. Three compounds, aglaiduline, 5-O-ethyl-hirsutanonol, and yakuchinone A, with good ADMET properties, acceptable Fit value and estimated value, and high docking score, were reserved for a molecular dynamics simulation study. All of them have stability of ligand binding. From our computational results, there might exhibit drug-like negative allosteric moderating effects on mGluR5 in these natural products. This work provides a reliable method for discovering mGluR5 NAMs from natural products.

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In Silico Discovery of Potential Azole-Containing mPGES-1 Inhibitors By Virtual Screening, Pharmacophore Modeling and Molecular Dynamics Simulations

10.21203/rs.3.rs-1228363/v1 ◽

2022 ◽

Author(s):

Lalehan Özalp ◽

İlkay Küçükgüzel ◽

Ayşe Ogan

Keyword(s):

Molecular Dynamics ◽

Side Effects ◽

Virtual Screening ◽

Correlation Coefficients ◽

Pharmacokinetic Profile ◽

Pharmacophore Modeling ◽

Dynamics Simulation ◽

Prostaglandin E ◽

Binding Modes ◽

Design Strategies

Abstract Inhibition of microsomal prostaglandin E2 synthase-1 (mPGES-1) is promising for designing novel nonsteroidal anti-inflammatory drugs, as they lack side-effects associated with inhibition of cyclooxygenase enzymes. Azole compounds are nitrogen-containing heterocycles and have a wide use in medicine and are considered as promising compounds in medicinal chemistry. Various computer-aided drug design strategies are incorporated in this study. Structure-based virtual screening was performed employing various docking programs. Receiver Operator Characteristic (ROC) curves were used to evaluate the selectivity of each program. Furthermore, scoring power of Autodock4 and Autodock Vina was assessed by Pearson’s correlation coefficients. Pharmacophore models were generated and Güner-Henry score of the best model was calculated as 0.89. Binding modes of the final 10 azole compounds were analyzed and further investigation of the best binding (-8.38 kcal/mol) compound was performed using molecular dynamics simulation, revealing that furazan1224 (ZINC001142847306) occupied the binding site of the substrate, prostaglandin H2 (PGH2) and remained stable for 100 ns. Continuous hydrogen bonds with amino acids in the active site supported the stability of furazan1224 throughout the trajectory. Pharmacokinetic profile showed that furazan1224 lacks the risks of inhibiting cytochrome P450 3A4 enzyme and central nervous system-related side-effects.

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Identification of Novel Chemical Entities for Adenosine Receptor Type 2A Using Molecular Modeling Approaches

Molecules ◽

10.3390/molecules25051245 ◽

2020 ◽

Vol 25 (5) ◽

pp. 1245 ◽

Cited By ~ 15

Author(s):

Kelton L. B. dos Santos ◽

Jorddy N. Cruz ◽

Luciane B. Silva ◽

Ryan S. Ramos ◽

Moysés F. A. Neto ◽

...

Keyword(s):

Molecular Dynamics ◽

Virtual Screening ◽

Adenosine Receptor ◽

Pharmacophore Model ◽

Qsar Model ◽

Positive Control ◽

Receptor Type ◽

Binding Modes

Adenosine Receptor Type 2A (A2AAR) plays a role in important processes, such as anti-inflammatory ones. In this way, the present work aimed to search for compounds by pharmacophore-based virtual screening. The pharmacokinetic/toxicological profiles of the compounds, as well as a robust QSAR, predicted the binding modes via molecular docking. Finally, we used molecular dynamics to investigate the stability of interactions from ligand-A2AAR. For the search for A2AAR agonists, the UK-432097 and a set of 20 compounds available in the BindingDB database were studied. These compounds were used to generate pharmacophore models. Molecular properties were used for construction of the QSAR model by multiple linear regression for the prediction of biological activity. The best pharmacophore model was used by searching for commercial compounds in databases and the resulting compounds from the pharmacophore-based virtual screening were applied to the QSAR. Two compounds had promising activity due to their satisfactory pharmacokinetic/toxicological profiles and predictions via QSAR (Diverset 10002403 pEC50 = 7.54407; ZINC04257548 pEC50 = 7.38310). Moreover, they had satisfactory docking and molecular dynamics results compared to those obtained for Regadenoson (Lexiscan®), used as the positive control. These compounds can be used in biological assays (in vitro and in vivo) in order to confirm the potential activity agonist to A2AAR.

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DISCOVERY AND EVALUATION OF POTENTIAL SONIC HEDGEHOG SIGNALING PATHWAY INHIBITORS USING PHARMACOPHORE MODELING AND MOLECULAR DYNAMICS SIMULATIONS

Journal of Bioinformatics and Computational Biology ◽

10.1142/s0219720011005732 ◽

2011 ◽

Vol 09 (supp01) ◽

pp. 15-35 ◽

Cited By ~ 9

Author(s):

SWAN HWANG ◽

SUNDARAPANDIAN THANGAPANDIAN ◽

YUNO LEE ◽

SUGUNADEVI SAKKIAH ◽

SHALINI JOHN ◽

...

Keyword(s):

Molecular Dynamics ◽

Signaling Pathway ◽

Sonic Hedgehog ◽

Active Site ◽

Hedgehog Signaling ◽

Structural Information ◽

Pharmacophore Modeling ◽

Binding Modes ◽

Shh Signaling ◽

Wide Range

Sonic hedgehog (Shh) plays an important role in the activation of Shh signaling pathway that regulates preservation and rebirth of adult tissues. An abnormal activation of this pathway has been identified in hyperplasia and various tumorigenesis. Hence the inhibition of this pathway using a Shh inhibitor might be an efficient way to treat a wide range of malignancies. This study was done in order to develop a lead chemical candidate that has an inhibitory function in the Shh signaling pathway. We have generated common feature pharmacophore models using three-dimensional (3D) structural information of robotnikinin, an inhibitor of the Shh signaling pathway, and its analogs. These models have been validated with fit values of robotnikinin and its analogs, and the best model was used as a 3D structural query to screen chemical databases. The hit compounds resulted from the screening docked into a proposed binding site of the Shh named pseudo-active site. Molecular dynamics (MD) simulations were performed to investigate detailed binding modes and molecular interactions between the hit compounds and functional residues of the pseudo-active site. The results of the MD simulation analyses revealed that the hit compounds can bind the pseudo-active site with high affinity than robotnikinin. As a result of this study, a candidate inhibitor (GK 03795) was selected as a potential lead to be employed in future Shh inhibitor design.

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Pharmacophore Modeling, Docking, and Molecular Dynamics Simulation of Flavonoids as Inhibitors of Urokinase-type Plasminogen Activator

Journal of Mathematical and Fundamental Sciences ◽

10.5614/j.math.fund.sci.2021.53.3.8 ◽

2022 ◽

Vol 53 (3) ◽

pp. 451-465

Author(s):

Daryono Hadi Tjahjono ◽

Bina Lohita Sari ◽

Slamet Ibrahim

Keyword(s):

Molecular Dynamics ◽

Binding Energy ◽

Plasminogen Activator ◽

Pharmacophore Model ◽

In Silico Analysis ◽

Pharmacophore Modeling ◽

Dynamics Simulation ◽

Type Plasminogen Activator ◽

Urokinase Type Plasminogen Activator ◽

The Stability

The urokinase-type plasminogen activator (uPA) system plays a significant role in the invasion and metastasis of cancer cells. The present study was conducted to investigate natural product compounds as inhibitors and hit molecules of uPA using in-silico analysis. A pharmacophore model was built to screen the Indonesian Herbal Database (HerbalDB) to obtain inhibitors of different scaffolds. Based on the molecular docking score, four ligands were selected as potential uPA inhibitors. Subsequently, the stability of the ligand-uPA complex was analyzed using molecular dynamics (MD) simulation. An RMSD graph of the backbone protein and the RMSF values of the amino acid residues were also determined. In addition, the MM-PBSA method was applied to calculate the free binding energy. According to the results, Model_3, characterized by aromatic rings 23 (F1 and F2), cationic H-bond donor (F3), and metal ligator (F4) features, had an adequate goodness-of-hit score (GH). The four top-ranked ligands, isorhamnetin, rhamnetin, quercetin, and kaempferol, showed higher docking scores compared to the others. This study confirmed that isorhamnetin, rhamnetin, and kaempferol build stable complexes with uPA with lower binding energy than quercetin.

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Structure-Based Pharmacophore Modeling, Virtual Screening, Molecular Docking, ADMET, and Molecular Dynamics (MD) Simulation of Potential Inhibitors of PD-L1 from the Library of Marine Natural Products

Marine Drugs ◽

10.3390/md20010029 ◽

2021 ◽

Vol 20 (1) ◽

pp. 29

Author(s):

Lianxiang Luo ◽

Ai Zhong ◽

Qu Wang ◽

Tongyu Zheng

Keyword(s):

Molecular Dynamics ◽

Natural Products ◽

Molecular Docking ◽

Virtual Screening ◽

Marine Natural Products ◽

Md Simulation ◽

Pharmacophore Model ◽

Pharmacophore Modeling ◽

Dynamics Simulation ◽

Stable Conformation

Background: In the past decade, several antibodies directed against the PD-1/PD-L1 interaction have been approved. However, therapeutic antibodies also exhibit some shortcomings. Using small molecules to regulate the PD-1/PD-L1 pathway may be another way to mobilize the immune system to fight cancer. Method: 52,765 marine natural products were screened against PD-L1(PDBID: 6R3K). To identify natural compounds, a structure-based pharmacophore model was generated, following by virtual screening and molecular docking. Then, the absorption, distribution, metabolism, and excretion (ADME) test was carried out to select the most suitable compounds. Finally, molecular dynamics simulation was also performed to validate the binding property of the top compound. Results: Initially, 13 small marine molecules were screened based on the pharmacophore model. Then, two compounds were selected for further evaluation based on the molecular docking scores. After ADME and toxicity studies, molecule 51320 was selected for further verification. By molecular dynamics analysis, molecule 51320 maintains a stable conformation with the target protein, so it has the chance to become an inhibitor of PD-L1. Conclusions: Through structure-based pharmacophore modeling, virtual screening, molecular docking, ADMET approaches, and molecular dynamics (MD) simulation, the marine natural compound 51320 can be used as a small molecule inhibitor of PD-L1.

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A Network of Phosphatidylinositol 4,5-bisphosphate Binding Sites Regulate Gating of the Ca2+-activated Cl− Channel ANO1 (TMEM16A)

10.1101/625897 ◽

2019 ◽

Cited By ~ 1

Author(s):

Kuai Yu ◽

Tao Jiang ◽

YuanYuan Cui ◽

Emad Tajkhorshid ◽

H. Criss Hartzell

Keyword(s):

Molecular Dynamics ◽

Protein Interactions ◽

Binding Sites ◽

Protein Function ◽

Computational Study ◽

Channel Gating ◽

Fluid Secretion ◽

Hydroxyl Groups ◽

Binding Modes ◽

Cytoplasmic Extension

AbstractANO1 (TMEM16A) is a Ca2+-activated Cl− channel that regulates diverse cellular functions including fluid secretion, neuronal excitability, and smooth muscle contraction. ANO1 is activated by elevation of cytosolic Ca2+ and modulated by phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2). Here we describe a closely concerted experimental and computational study, including electrophysiology, mutagenesis, functional assays, and extended sampling of lipid-protein interactions with molecular dynamics (MD) to characterize PI(4,5)P2 binding modes and sites on ANO1. ANO1 currents in excised inside-out patches activated by 270 nM Ca2+ at +100 mV are increased by exogenous PI(4,5)P2 with an EC50 = 1.24 µM. The effect of PI(4,5)P2 is dependent on membrane voltage and Ca2+ and is explained by a stabilization of the ANO1 Ca2+-bound open state. Unbiased atomistic MD simulations with 1.4 mol% PI(4,5)P2 in a phosphatidylcholine bilayer identified 8 binding sites with significant probability of binding PI(4,5)P2. Three of these sites captured 85% of all ANO1 - PI(4,5)P2 interactions. Mutagenesis of basic amino acids near the membrane-cytosol interface found three regions of ANO1 critical for PI(4,5)P2 regulation that correspond to the same three sites identified by MD. PI(4,5)P2 is stabilized by hydrogen bonding between amino acid sidechains and phosphate/hydroxyl groups on PI(4,5)P2. Binding of PI(4,5)P2 alters the position of the cytoplasmic extension of TM6, which plays a crucial role in ANO1 channel gating, and increases the accessibility of the inner vestibule to Cl−ions. We propose a model consisting of a network of three PI(4,5)P2 binding sites at the cytoplasmic face of the membrane allosterically regulating ANO1 channel gating.Significance statementMembrane proteins dwell in a sea of phospholipids that not only structurally stabilize the proteins by providing a hydrophobic environment for their transmembrane segments, but also dynamically regulate protein function. While many cation channels are known to be regulated by phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), relatively little is known about anion channel regulation by phosphoinositides. Using a combination of patch clamp electrophysiology and atomistic molecular dynamics simulations, we have identified several PI(4,5)P2 binding sites in ANO1 (TMEM16A), a Cl− channel that performs myriad physiological functions from epithelial fluid secretion to regulation of electrical excitability. These binding sites form a band at the cytosolic interface of the membrane that we propose constitute a network to dynamically regulate this highly allosteric protein.

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An overview of in silico methods used in the design of VEGFR-2 inhibitors as anticancer agents

Physical Sciences Reviews ◽

10.1515/psr-2018-0163 ◽

2022 ◽

Vol 0 (0) ◽

Author(s):

Richie R. Bhandare ◽

Bulti Bakchi ◽

Dilep Kumar Sigalapalli ◽

Afzal B. Shaik

Keyword(s):

Drug Design ◽

Molecular Interactions ◽

Anticancer Agents ◽

In Silico ◽

Pharmacophore Modeling ◽

Rational Drug Design ◽

Promising Target ◽

Rational Drug ◽

Respective Protein ◽

In Silico Methods

Abstract VEGFR-2 enzyme known for physiological functioning of the cell also involves in pathological angiogenesis and tumor progression. Recently VEGFR-2 has gained the interest of researchers all around the world as a promising target for the drug design and discovery of new anticancer agents. VEGFR2 inhibitors are a major class of anticancer agents used for clinical purposes. In silico methods like virtual screening, molecular docking, molecular dynamics, pharmacophore modeling, and other computational approaches help extensively in identifying the main molecular interactions necessary for the binding of the small molecules with the respective protein target to obtain the expected pharmacological potency. In this chapter, we discussed some representative case studies of in silico techniques used to determine molecular interactions and rational drug design of VEGFR-2 inhibitors as anticancer agents.

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