Structural and dynamical aspects of Streptococcus gordonii FabH through molecular docking and MD simulations

Shamim, Amen; Abbasi, Sumra Wajid; Azam, Syed Sikander

doi:10.1016/j.jmgm.2015.05.013

Cited by 12 publications

(6 citation statements)

References 86 publications

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“…A threshold of 2.5 and 3.0 Å were used for hydrogen bonds and van der Waals bond distances, respectively. The conformation of a ligand was evaluated by scoring function GoldScore, ChemScore, Astex Statistical Potential (ASP), and ChemPLP score . The best-docked complexes were selected based on their highest GoldScore.…”

Section: Methodsmentioning

confidence: 99%

“…The conformation of a ligand was evaluated by scoring function GoldScore, ChemScore, Astex Statistical Potential (ASP), and ChemPLP score. 65 The bestdocked complexes were selected based on their highest GoldScore. GoldScore also known as fitness function and it used as scoring functions that is made up of four components: where, S (hb ext ) (H bonding) and S (vdw ext ) (van der Waals) are interactions between protein and ligand.…”

Section: ■ Materials and Methodsmentioning

confidence: 99%

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Deciphering the Inhibition Mechanism of under Trial Hsp90 Inhibitors and Their Analogues: A Comparative Molecular Dynamics Simulation

Nazar

Abbas

Azam

2020

J. Chem. Inf. Model.

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Heat shock protein 90 (Hsp90) performs functions in cellular activities together with other signaling pathways. Hsp90 is evolutionarily conserved and universally articulated as a human cancer-causing agent involved in lung cancer and breast cancer followed by colon and rectum cancers. It has emerged as an effective drug candidate, and inhibition may affect several signaling pathways associated with cancer spread. Therefore, in-silico approaches, molecular docking, molecular dynamics simulation, and binding free energy calculations were applied to create insights into the inhibition mechanism against Hsp90 to identify new cancer therapeutic drugs. Top-docked Hsp90-inhibitor complexes with their analogues were selected as the best complexes based on the GOLD fitness score and orientation. The significant interaction of Hsp90 inhibitors and their analogues were observed to be bound with active site residues as well as residing within the same cavity region. System stability factors RMSD, RMSF, beta-factor, and radius of gyration were analyzed for top-docked complexes and ensure strong binding interaction between inhibitors and the Hsp90 cavity. Cavity bound inhibitors were found to retain consistent hydrogen bonding during the simulation. The radial distribution function (RDF) illustrated that interacting active site residues drive the binding and stability of the inhibitors. Similarly, the axial frequency distribution, which is an indigenously developed analytical tool, produced noteworthy knowledge of the hydrogen-bonding pattern. Results yielded new insights into the design of cancer therapeutic drugs against Hsp90. This finding suggests that under trial Hsp90 inhibitors MPC-3100 could be a potential starting point into the development of potential anticancer agents with the possibility of future directions for the improvement of early existing Hsp90 inhibitors CNF-2024 and SNX-5422 as an anticancer agent.

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Section: Methodsmentioning

confidence: 99%

Section: ■ Materials and Methodsmentioning

confidence: 99%

Deciphering the Inhibition Mechanism of under Trial Hsp90 Inhibitors and Their Analogues: A Comparative Molecular Dynamics Simulation

Nazar

Abbas

Azam

2020

J. Chem. Inf. Model.

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“…The Cα atoms reached a consistent fluctuation only after 0.5Å and was maintained all through the model. There was no drastic increase in RMSD value, possibly indicating stability of these two systems [42]. Quercetagetin complex, on other hand, showed a steady state from 15ns to 78ns and the oscillation was between 1.6 Å and 3.2 Å.…”

Section: Discussionmentioning

confidence: 89%

Molecular docking, simulation and binding free energy analysis of small molecules as PfHT1 inhibitors

Owoloye

Ligali

Enejoh

et al. 2022

Preprint

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Malaria chemotherapy has been plagued by parasite resistance. Novel drugs must be continually explored for malaria treatment. Plasmodium falciparum requires host glucose for survival and proliferation. Protein involved in hexose permeation, P. falciparum hexose transporter 1 (PfHT1) is a potential drug target. We performed high throughput virtual screening of 21,352 small-molecule compounds against PfHT1. The stability of the lead compound complexes was evaluated via molecular dynamics (MD) simulation for 100 nanoseconds. We also investigated the pharmacodynamic, pharmacokinetic and physiological characteristics of the compounds in accordance with Lipinksi rules for drug-likeness to bind and inhibit PfHT1. Molecular docking and free binding energy analyses were carried out using Molecular Mechanics with Generalised Born and Surface Area (MMGBSA) solvation to determine the selectivity of the hit compounds for PfHT1 over the human glucose transporter (hGLUT1) orthologue. Five important compounds were identified: Hyperoside (CID5281643); avicularin (CID5490064); sylibin (CID5213); harpagoside (CID5481542) and quercetagetin (CID5281680). The compounds formed intermolecular interaction with the binding pocket of the target via conserved amino acid residues (Val314, Gly183, Thr49, Asn52, Gly183, Ser315, Ser317, and Asn48). The MMGBSA analysis of the complexes yielded high free binding energies. Four (CID5281643, CID5490064, CID5213, and CID5481542) of the identified compounds were found to be stable within the PfHT1 binding pocket throughout the 100 nanoseconds simulation run time. The four compounds demonstrated higher affinity for PfHT1 than the human major glucose transporter (hGLUT1). This investigation demonstrates the inhibition potential of sylibin, hyperoside, harpagoside, and avicularin against PfHT1 receptor. Robust preclinical investigations are required to validate the chemotherapeutic properties of the identified compounds.

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“…β ‐Ketoacyl acyl carrier protein synthase III (KAS III) catalyzes the condensation reaction between acyl‐CoA and malonyl‐ACP during fatty acid biosynthesis . The active site of FabH consists of the catalytic triad formed by the residues Cys117, His250 and Asn280 in which Cys117 is involved in acetyl transfer, while His250 and Asn280 play an active role in decarboxylation . Thus, it is important to note that 10a interacts with this catalytic triad via forming three hydrogen bonds.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Disulfide‐Bridged N‐Phenyl‐N′‐(alkyl/aryl/heteroaryl)urea Derivatives and Evaluation of Their Antimicrobial Activities

Doğan

Buran

Gündüz

et al. 2019

Chemistry & Biodiversity

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The discovery of new antimicrobial agents is extremely needed to overcome multidrug-resistant bacterial and tuberculosis infections. In the present study, eight novel substituted urea derivatives (10a-10h) containing disulfide bond were designed, synthesized and screened for their in vitro antimicrobial activities on standard strains of Gram-positive and Gram-negative bacteria as well as on Mycobacterium tuberculosis. According to the obtained results, antibacterial effects of the compounds were found to be considerably better than their antimycobacterial activities along with their weak cytotoxic effects. Molecular docking studies were performed to gain insights into the antibacterial activity mechanism of the synthesized compounds. The interactions and the orientation of compound 10a (1,1'-((disulfanediylbis(methylene))bis(2,1-phenylene))bis(3-phenylurea)) were found to be highly similar to the original ligand within the binding pocket E. faecalis β-ketoacyl acyl carrier protein synthase III (FabH). Finally, a theoretical study was established to predict the physicochemical properties of the compounds. Scheme 1. Synthetic scheme for the preparation of the key compound, 2,2'-[disulfanediylbis(methylene)]dibenzoic acid (5).

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Structural and dynamical aspects of Streptococcus gordonii FabH through molecular docking and MD simulations

Cited by 12 publications

References 86 publications

Deciphering the Inhibition Mechanism of under Trial Hsp90 Inhibitors and Their Analogues: A Comparative Molecular Dynamics Simulation

Deciphering the Inhibition Mechanism of under Trial Hsp90 Inhibitors and Their Analogues: A Comparative Molecular Dynamics Simulation

Molecular docking, simulation and binding free energy analysis of small molecules as PfHT1 inhibitors

Synthesis of Disulfide‐Bridged N‐Phenyl‐N′‐(alkyl/aryl/heteroaryl)urea Derivatives and Evaluation of Their Antimicrobial Activities

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