Testing Assumptions and Hypotheses for Rescoring Success in Protein−Ligand Docking

Protein-ligand docking programs are indispensable tools for predicting the binding pose of a ligand to the receptor protein in current structure-based drug design. In this paper, we evaluate the performance of grey wolf optimization (GWO) in protein-ligand docking. Two versions of the GWO docking program – the original GWO and the modified one with random walk – were implemented based on AutoDock Vina. Our rigid docking experiments show that the GWO programs have enhanced exploration capability leading to significant speedup in the search while maintaining comparable binding pose prediction accuracy to AutoDock Vina. For flexible receptor docking, the GWO methods are competitive in pose ranking but lower in success rates than AutoDockFR. Successful redocking of all the flexible cases to their holo structures reveals that inaccurate scoring function and lack of proper treatment of backbone are the major causes of docking failures.

DPP-IV Inhibitory Phenanthridines: Ligand, Structure-Based Design and Synthesis

Current Computer - Aided Drug Design ◽

10.2174/1573409915666181211114743 ◽

2020 ◽

Vol 16 (3) ◽

pp. 295-307

Author(s):

Reema A. Khalaf ◽

Dalal Masalha ◽

Dima Sabbah

Keyword(s):

Pharmacophore Model ◽

Pharmacophore Modeling ◽

Ligand Docking ◽

Health Concern ◽

Aromatic Rings ◽

Oral Antidiabetic Agents ◽

Design And Synthesis ◽

Dpp Iv ◽

Novel Scaffold

Background: Lately, diabetes has become the main health concern for millions of people around the world. Dipeptidyl peptidase-IV (DPP-IV) inhibitors have emerged as a new class of oral antidiabetic agents. Formerly, acridines, N4-sulfonamido-succinamic, phthalamic, acrylic and benzoyl acetic acid derivatives, and sulfamoyl-phenyl acid esters were designed and developed as new DPP-IV inhibitors. Objective: This study aims to develop a pharmacophore model of DPP-IV inhibitors and to evaluate phenanthridines as a novel scaffold for inhibiting DPP-IV enzyme. In addition, to assess their binding interactions with the enzyme through docking in the binding site of 4A5S (PDB). Methods: Herein, Quantum–Polarized Ligand Docking (QPLD) and ligand-based pharmacophore modeling investigations were performed. Three novel 3,8-disubstituted-6-phenyl phenanthridine derivatives 3-5 have been designed, synthesized and characterized. In vitro biological testing against DPP-IV was carried out using fluorometric assay kit. Results: QPLD study demonstrates that compounds 3-5 forms H-bond with Lys554, Trp629, and Tyr631, besides charge transfer interaction between their aromatic rings and the aromatic rings of Tyr547 and Tyr666. Moreover, they fit the three pharmacophoric point features of DPP-IV inhibitors and were proven to have in vitro DPP-IV inhibitory activity where compound 5 displayed a % inhibition of 45.4 at 100 μM concentration. Conclusion: Phenanthridines may serve as a potential lead compound for developing new DPP-IV inhibitors as a promising antidiabetic agent. Computational results suggest future structural simplification.

Application of Molecular Docking for the Development of Improved HIV-1 Reverse Transcriptase Inhibitors

Current Computer - Aided Drug Design ◽

10.2174/1573409916666200628103359 ◽

2020 ◽

Vol 16 ◽

Author(s):

Arash Soltani ◽

Seyed Isaac Hashemy ◽

Farnaz Zahedi Avval ◽

Houshang Rafatpanah ◽

Seyed Abdolrahim Rezaee ◽

...

Keyword(s):

Reverse Transcriptase ◽

Binding Capacity ◽

Binding Pocket ◽

Ligand Docking ◽

Binding Modes ◽

Wild Type ◽

Parent Molecule ◽

Discovery Studio ◽

Approved Drugs ◽

Hiv 1

Introoduction: Inhibition of the reverse transcriptase (RT) enzyme of human immunodeficiency virus (HIV) by low molecular weight inhibitors is still an active area of research. Here, protein-ligand interactions and possible binding modes of novel compounds with the HIV-1 RT binding pocket (the wild-type as well as Y181C and K103N mutants) were obtained and discussed. Methods: A molecular fragment-based approach using FDA-approved drugs were followed to design novel chemical derivatives using delavirdine, efavirenz, etravirine and rilpivirine as the scaffolds. The drug-likeliness of the derivatives was evaluated using Swiss-ADME. Then the parent molecule and derivatives were docked into the binding pocket of related crystal structures (PDB ID: 4G1Q, 1IKW, 1KLM and 3MEC). Genetic Optimization for Ligand Docking (GOLD) Suite 5.2.2 software was used for docking and the results analyzed in the Discovery Studio Visualizer 4. A derivative was chosen for further analysis, if it passed drug-likeliness and the docked energy was more favorable than that of its parent molecule. Out of the fifty-seven derivatives, forty-eight failed in druglikeness screening by Swiss-ADME or in docking stage. Results: The final results showed that the selected compounds had higher predicted binding affinities than their parent scaffolds in both wild-type and the mutants. Binding energy improvement was higher for the structures designed based on second-generation NNRTIs (etravirine and rilpivirine) than the first-generation NNRTIs (delavirdine and efavirenz). For example, while the docked energy for rilpivirine was -51 KJ/mol, it was improved for its derivatives RPV01 and RPV15 up to -58.3 and -54.5 KJ/mol, respectively. Conclusion: In this study, we have identified and proposed some novel molecules with improved binding capacity for HIV RT using fragment-based approach.

Phenanthridine Sulfonamide Derivatives as Potential DPP-IV Inhibitors: Design, Synthesis and Biological Evaluation

Current Computer - Aided Drug Design ◽

10.2174/1573409916666201007124122 ◽

2020 ◽

Vol 16 ◽

Author(s):

Reema Abu Khalaf ◽

Shorooq Alqazaqi ◽

Maram Aburezeq ◽

Dima Sabbah ◽

Ghadeer Albadawi ◽

...

Keyword(s):

Inhibitory Activity ◽

Biological Evaluation ◽

Ligand Docking ◽

Biological Assessment ◽

Hypoglycemic Agents ◽

Binding Affinities ◽

Oral Hypoglycemic Agents ◽

Design Synthesis ◽

Dpp Iv

Background: Diabetes mellitus is a chronic metabolic disorder, characterized by hyperglycemia over a prolonged period, disturbance of fat, protein and carbohydrate metabolism, resulting from defective insulin secretion, insulin action or both. Dipeptidyl peptidase-IV (DPP-IV) inhibitors are relatively a new class of oral hypoglycemic agents that reduces the deterioration of gut-derived endogenous incretin hormones that are secreted in response to food ingestion to stimulate the secretion of insulin from beta cells of pancreas. Objective: In this study, synthesis, characterization, and biological assessment of twelve novel phenanthridine sulfonamide derivatives 3a-3l as potential DPP-IV inhibitors was carried out. The target compounds were docked to study the molecular interactions and binding affinities against DPP-IV enzyme. Methods: The synthesized molecules were characterized using 1H-NMR, 13C-NMR, IR, and MS. Quantum-polarized ligand docking (QPLD) was also performed. Results: In vitro biological evaluation of compounds 3a-3l reveals comparable DPP-IV inhibitory activities ranging from 10%-46% at 100 µM concentration, where compound 3d harboring ortho-fluoro moiety exhibited the highest inhibitory activity. QPLD study shows that compounds 3a-3l accommodate DPP-IV binding site and form H-bonding with the R125, E205, E206, S209, F357, R358, K554, W629, S630, Y631, Y662, R669 and Y752 backbones. Conclusion: In conclusion, phenanthridine sulfonamides could serve as potential DPP-IV inhibitors that require further structural optimization in order to enhance their inhibitory activity.

Mutation-Based Antibiotic Resistance Mechanism in Methicillin-Resistant Staphylococcus aureus Clinical Isolates

Pharmaceuticals ◽

10.3390/ph14050420 ◽

2021 ◽

Vol 14 (5) ◽

pp. 420

Author(s):

Tanveer Ali ◽

Abdul Basit ◽

Asad Mustafa Karim ◽

Jung-Hun Lee ◽

Jeong-Ho Jeon ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Antibiotic Resistance ◽

Active Site ◽

Methicillin Resistant Staphylococcus Aureus ◽

Meca Gene ◽

Resistance Mechanism ◽

Ligand Docking ◽

Clinical Samples ◽

Allosteric Site ◽

Methicillin Resistant

β-Lactam antibiotics target penicillin-binding proteins and inhibit the synthesis of peptidoglycan, a crucial step in cell wall biosynthesis. Staphylococcus aureus acquires resistance against β-lactam antibiotics by producing a penicillin-binding protein 2a (PBP2a), encoded by the mecA gene. PBP2a participates in peptidoglycan biosynthesis and exhibits a poor affinity towards β-lactam antibiotics. The current study was performed to determine the diversity and the role of missense mutations of PBP2a in the antibiotic resistance mechanism. The methicillin-resistant Staphylococcus aureus (MRSA) isolates from clinical samples were identified using phenotypic and genotypic techniques. The highest frequency (60%, 18 out of 30) of MRSA was observed in wound specimens. Sequence variation analysis of the mecA gene showed four amino acid substitutions (i.e., E239K, E239R, G246E, and E447K). The E239R mutation was found to be novel. The protein-ligand docking results showed that the E239R mutation in the allosteric site of PBP2a induces conformational changes in the active site and, thus, hinders its interaction with cefoxitin. Therefore, the present report indicates that mutation in the allosteric site of PBP2a provides a more closed active site conformation than wide-type PBP2a and then causes the high-level resistance to cefoxitin.

Modeled 3D-Structures of Proteobacterial Transglycosylases from Glycoside Hydrolase Family 17 Give Insight in Ligand Interactions Explaining Differences in Transglycosylation Products

Applied Sciences ◽

10.3390/app11094048 ◽

2021 ◽

Vol 11 (9) ◽

pp. 4048

Author(s):

Javier A. Linares-Pastén ◽

Lilja Björk Jonsdottir ◽

Gudmundur O. Hreggvidsson ◽

Olafur H. Fridjonsson ◽

Hildegard Watzlawick ◽

...

Keyword(s):

Glycoside Hydrolase ◽

Ligand Docking ◽

Glycoside Hydrolase Family ◽

Ligand Interactions ◽

Tim Barrel ◽

Branching Point ◽

The Difference ◽

Dynamics Simulations ◽

And Function ◽

Hydrolase Family

The structures of glycoside hydrolase family 17 (GH17) catalytic modules from modular proteins in the ndvB loci in Pseudomonas aeruginosa (Glt1), P. putida (Glt3) and Bradyrhizobium diazoefficiens (previously B. japonicum) (Glt20) were modeled to shed light on reported differences between these homologous transglycosylases concerning substrate size, preferred cleavage site (from reducing end (Glt20: DP2 product) or non-reducing end (Glt1, Glt3: DP4 products)), branching (Glt20) and linkage formed (1,3-linkage in Glt1, Glt3 and 1,6-linkage in Glt20). Hybrid models were built and stability of the resulting TIM-barrel structures was supported by molecular dynamics simulations. Catalytic amino acids were identified by superimposition of GH17 structures, and function was verified by mutagenesis using Glt20 as template (i.e., E120 and E209). Ligand docking revealed six putative subsites (−4, −3, −2, −1, +1 and +2), and the conserved interacting residues suggest substrate binding in the same orientation in all three transglycosylases, despite release of the donor oligosaccharide product from either the reducing (Glt20) or non-reducing end (Glt1, Gl3). Subsites +1 and +2 are most conserved and the difference in release is likely due to changes in loop structures, leading to loss of hydrogen bonds in Glt20. Substrate docking in Glt20 indicate that presence of covalently bound donor in glycone subsites −4 to −1 creates space to accommodate acceptor oligosaccharide in alternative subsites in the catalytic cleft, promoting a branching point and formation of a 1,6-linkage. The minimum donor size of DP5, can be explained assuming preferred binding of DP4 substrates in subsite −4 to −1, preventing catalysis.

Evaluating Variants of Firefly Algorithm for Ligand Pose Prediction in Protein-ligand Docking Program

Proceedings of the 2020 12th International Conference on Bioinformatics and Biomedical Technology ◽

10.1145/3405758.3405761 ◽

2020 ◽

Author(s):

Meng Chi Ao ◽

Shirley W. I. Siu

Keyword(s):

Firefly Algorithm ◽

Ligand Docking ◽

Pose Prediction ◽

Docking Program

Necrostatin-1 Analog DIMO Exerts Cardioprotective Effect against Ischemia Reperfusion Injury by Suppressing Necroptosis via Autophagic Pathway in Rats

Pharmacology ◽

10.1159/000510864 ◽

2021 ◽

Vol 106 (3-4) ◽

pp. 189-201

Author(s):

Shigang Qiao ◽

Wen-jie Zhao ◽

Huan-qiu Li ◽

Gui-zhen Ao ◽

Jian-zhong An ◽

...

Keyword(s):

Cell Death ◽

Ischemia Reperfusion Injury ◽

Myocardial Infarct ◽

Ischemia Reperfusion ◽

Glucose Deprivation ◽

Neonatal Rat ◽

Ligand Docking ◽

Autophagic Flux ◽

Myocardial Infarct Size ◽

Rat Cardiomyocytes

Aim: It has been reported that necrostatin-1 (Nec-1) is a specific necroptosis inhibitor that could attenuate programmed cell death induced by myocardial ischemia/reperfusion (I/R) injury. This study aimed to observe the effect and mechanism of novel Nec-1 analog (Z)-5-(3,5-dimethoxybenzyl)-2-imine-1-methylimidazolin-4-1 (DIMO) on myocardial I/R injury. Methods: Male SD rats underwent I/R injury with or without different doses of DIMO (1, 2, or 4 mg/kg) treatment. Isolated neonatal rat cardiomyocytes were subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) treatment with or without DIMO (0.1, 1, 10, or 100 μM). Myocardial infarction was measured by TTC staining. Cardiomyocyte injury was assessed by lactate dehydrogenase assay (LDH) and flow cytometry. Receptor-interacting protein 1 kinase (RIP1K) and autophagic markers were detected by co-immunoprecipitation and Western blotting analysis. Molecular docking of DIMO into the ATP binding site of RIP1K was performed using GLIDE. Results: DIMO at doses of 1 or 2 mg/kg improved myocardial infarct size. However, the DIMO 4 mg/kg dose was ineffective. DIMO at the dose of 0.1 μM decreased LDH leakage and the ratio of PI-positive cells followed by OGD/R treatment. I/R or OGD/R increased RIP1K expression and in its interaction with RIP3K, as well as impaired myocardial autophagic flux evidenced by an increase in LC3-II/I ratio, upregulated P62 and Beclin-1, and activated cathepsin B and L. In contrast, DIMO treatment reduced myocardial cell death and reversed the above mentioned changes in RIP1K and autophagic flux caused by I/R and OGD/R. DIMO binds to RIP1K and inhibits RIP1K expression in a homology modeling and ligand docking. Conclusion: DIMO exerts cardioprotection against I/R- or OGD/R-induced injury, and its mechanisms may be associated with the reduction in RIP1K activation and restoration impaired autophagic flux.

GalaxyDock2: Protein-ligand docking using beta-complex and global optimization

Journal of Computational Chemistry ◽

10.1002/jcc.23438 ◽

2013 ◽

Vol 34 (30) ◽

pp. 2647-2656 ◽

Cited By ~ 40

Author(s):

Woong-Hee Shin ◽

Jae-Kwan Kim ◽

Deok-Soo Kim ◽

Chaok Seok

Keyword(s):

Global Optimization ◽

Ligand Docking

Identification of New Potential Inhibitors of Quorum Sensing through a Specialized Multi-Level Computational Approach

Molecules ◽

10.3390/molecules26092600 ◽

2021 ◽

Vol 26 (9) ◽

pp. 2600

Author(s):

Fábio G. Martins ◽

André Melo ◽

Sérgio F. Sousa

Keyword(s):

Virtual Screening ◽

Quorum Sensing ◽

In Silico ◽

Bacterial Infections ◽

Extracellular Polymeric Substances ◽

Free Energy Calculations ◽

Ligand Docking ◽

Screening Tests ◽

Scoring Functions ◽

Potential Inhibitors

Biofilms are aggregates of microorganisms anchored to a surface and embedded in a self-produced matrix of extracellular polymeric substances and have been associated with 80% of all bacterial infections in humans. Because bacteria in biofilms are less amenable to antibiotic treatment, biofilms have been associated with developing antibiotic resistance, a problem that urges developing new therapeutic options and approaches. Interfering with quorum-sensing (QS), an important process of cell-to-cell communication by bacteria in biofilms is a promising strategy to inhibit biofilm formation and development. Here we describe and apply an in silico computational protocol for identifying novel potential inhibitors of quorum-sensing, using CviR—the quorum-sensing receptor from Chromobacterium violaceum—as a model target. This in silico approach combines protein-ligand docking (with 7 different docking programs/scoring functions), receptor-based virtual screening, molecular dynamic simulations, and free energy calculations. Particular emphasis was dedicated to optimizing the discrimination ability between active/inactive molecules in virtual screening tests using a target-specific training set. Overall, the optimized protocol was used to evaluate 66,461 molecules, including those on the ZINC/FDA-Approved database and to the Mu.Ta.Lig Virtual Chemotheca. Multiple promising compounds were identified, yielding good prospects for future experimental validation and for drug repurposing towards QS inhibition.