QM/MM Calculations in Drug Discovery: A Useful Method for Studying Binding Phenomena?

Gleeson, M. Paul; Gleeson, Duangkamol

doi:10.1021/ci800419j

Cited by 81 publications

(50 citation statements)

References 60 publications

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“…As a motivation of this work the authors claimed 23 that an involvement of the second water molecule in the catalytic mechanism was prompted by the cryotechnique studies by Scheidig, Burmester and Goody et al 38 This is an improper reference since in the latter work the GTP hydrolysis in Ras, but not in Ras-GAP has been experimentally studied. 39 The conclusions from the computations 23 suggesting that two water molecules operate in the cavity of the Ras·GTP·GAP complex are doubtful because of application of the semiempirical PM3…”

Section: New Piecesmentioning

confidence: 99%

See 1 more Smart Citation

Hydrolysis of Guanosine Triphosphate (GTP) by the Ras·GAP Protein Complex: Reaction Mechanism and Kinetic Scheme

et al. 2015

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Molecular mechanisms of hydrolysis of guanosine triphosphate (GTP) to guanosine diphosphate (GDP) and inorganic phosphate (Pi) by the Ras·GAP protein complex are fully investigated by using modern modeling tools. The previously hypothesized stages of the cleavage of the phosphorus-oxygen bond in GTP and the formation of the imide form of catalytic Gln61 from Ras upon creation of Pi are confirmed by using the higher-level quantum-based calculations. The steps of the enzyme regeneration are modeled for the first time, providing a comprehensive description of the catalytic cycle. It is found that for the reaction Ras·GAP·GTP·H 2 O → Ras·GAP·GDP·Pi the highest barriers correspond to the process of regeneration of the active site, but not to the process of substrate cleavage. The specific shape of the energy profile is responsible for an interesting kinetic mechanism of the GTP hydrolysis. The analysis of the process using the first-passage approach and consideration of kinetic equations suggest that the overall reactions rate is a result of the balance between relatively fast transitions and low probability of states from which these transitions are taking place. Our theoretical predictions are in excellent agreement with available experimental observations on GTP hydrolysis rates.3

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Section: New Piecesmentioning

confidence: 99%

“…Shortcomings of the PM3 methodology in describing hydrogen bonds, which is crucial for modeling protein systems, are well-known, e.g. ; 39 by these reasons more advanced procedures above PM3 have been introduced recent years. 40,41 Most likely, the protein structures obtained in Ref.…”

Section: New Piecesmentioning

confidence: 99%

Hydrolysis of Guanosine Triphosphate (GTP) by the Ras·GAP Protein Complex: Reaction Mechanism and Kinetic Scheme

et al. 2015

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“…This was an exhaustive procedure that took several days to finish. QM/MM has been shown to be a powerful tool for improving protein crystal structures [39], and it has proven reliable for studying protein-ligand binding phenomena [40].…”

Section: Qm/mm-pb/sa Can Accurately Reproduce the Biological Activitimentioning

confidence: 99%

Testing the sensitivities of noncognate inhibitors to varicella zoster virus thymidine kinase: implications for postherpetic neuralgia therapy with existing agents

Yang

et al. 2014

J Mol Model

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Varicella zoster virus (VZV), a member of the human herpesvirus family, affects peripheral or cranial nerves and can reactivate years after the primary infection. Thymidine kinase (TK) is essential for VZV replication, and its active site is highly conserved in the herpesvirus family. A number of small-molecule inhibitors have already been successfully developed that target the TK of herpes simplex virus type 1 (HSV-1), which is one of the most prevalent sexually transmitted infections worldwide. In the present study, we attempted to test the sensitivities of HSV-1 TK inhibitors to their noncognate VZV TK by integrating in silico modeling and an in vitro assay. We tested nine representative HSV-1 TK inhibitors, including three FDA-approved drugs and six compounds that are under clinical development. The structures of the complexes of these inhibitor ligands with HSV-1 TK and noncognate VZV TK had been solved previously by X-ray crystallography or were modeled in the present work using a template-based approach. Subsequently, a rigorous quantum mechanics/molecular mechanics (QM/MM) nonbonded analysis that accounted for the Poisson-Boltzmann/surface area (PB/SA) solvent effect was employed to refine the complex structures and, on this basis, to evaluate the binding potencies of these complexes. As might be expected, the QM/MM-PB/SA-derived free energy was shown to be highly correlated with the HSV-1 TK inhibitory activities of the nine inhibitors. Further, it was found that the HSV-1 TK inhibitors exhibit strong binding affinities for their noncognate VZV TK, although they are still more selective for HSV-1 TK than for VZV TK. In order to test the theoretical results obtained from the computational analysis, we performed an in vitro kinase assay to determine the inhibitory potencies of three commercially available antiviral agents, namely penciclovir, ganciclovir, and aciclovir, against their noncognate target VZV TK, resulting in IC50 values of 86, 127, and 150 μM respectively, which are modestly weaker than the corresponding values obtained for HSV-1 TK. In addition, visual structure examination and virtual mutation/deletion analysis suggested that the residue Arg222 is present at the active site of HSV-1 TK but not at the active site of VZV TK, which is the reason for the difference in inhibitor selectivity between HSV-1 TK and VZV TK.

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“…QM/MM can be used for preparing the structures of small molecules and proteins, such as optimizing the binding poses obtained from docking [37], and refining the geometries of enzyme active sites obtained from a harmonically restrained minimization with MM [38], or X-ray structures [39]. It has been suggested that within the drug discovery process QM/MM is valuable for (1) helping the interpretation of poorly resolved electron density [39], (2) probing the details of the interactions within enzymes active sites, [40] and (3) investigating the effects of different substituents on the binding mode or in the assessment of alternate scaffolds [41].…”

Section: Qm/mmmentioning

confidence: 99%

Quantum Mechanical Methods for Drug Design

Zhou

Huang

Caflisch

2010

CTMC

111

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Quantum mechanical (QM) methods are becoming popular in computational drug design and development mainly because high accuracy is required to estimate (relative) binding affinities. For low-to medium-throughput in silico screening, (e.g., scoring and prioritizing a series of inhibitors sharing the same molecular scaffold) efficient approximations have been developed in the past decade, like linear scaling QM in which the computation time scales almost linearly with the number of basis functions. Furthermore, QM-based procedures have been used recently for determining protonation states of ionizable groups, evaluating energies, and optimizing molecular structures. For high-throughput in silico screening QM approaches have been employed to derive robust quantitative structure-activity relationship models. It is expected that the use of QM methods will keep growing in all phases of computer-aided drug design and development. However, extensive sampling of conformational space and treatment of solution of macromolecules are still limiting factors for the broad application of QM in drug design.

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QM/MM Calculations in Drug Discovery: A Useful Method for Studying Binding Phenomena?

Cited by 81 publications

References 60 publications

Hydrolysis of Guanosine Triphosphate (GTP) by the Ras·GAP Protein Complex: Reaction Mechanism and Kinetic Scheme

Hydrolysis of Guanosine Triphosphate (GTP) by the Ras·GAP Protein Complex: Reaction Mechanism and Kinetic Scheme

Testing the sensitivities of noncognate inhibitors to varicella zoster virus thymidine kinase: implications for postherpetic neuralgia therapy with existing agents

Quantum Mechanical Methods for Drug Design

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