Calculation of solvation and binding free energy differences between VX-478 and its analogs by free energy perturbation and AMSOL methods

Rao, B. Govinda; Kim, E. E.; Murcko, Mark A.

doi:10.1007/bf00124462

Cited by 31 publications

(23 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Freeenergy perturbation and thermodynamic integration methods have been shown to determine free energy change within 1 kcal/ mol of the experimental values; hence they afford high accuracy (43). The thermodynamic integration approach takes into consideration several factors that are important for the accurate calculations of the pK a of ionizable groups.…”

Section: Resultsmentioning

confidence: 99%

The Importance of a Critical Protonation State and the Fate of the Catalytic Steps in Class A β-Lactamases and Penicillin-binding Proteins

Golemi-Kotra

Meroueh

Kim

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

␤-Lactamases and penicillin-binding proteins are bacterial enzymes involved in antibiotic resistance to ␤-lactam antibiotics and biosynthetic assembly of cell wall, respectively. Members of these large families of enzymes all experience acylation by their respective substrates at an active site serine as the first step in their catalytic activities. A Ser-X-X-Lys sequence motif is seen in all these proteins, and crystal structures demonstrate that the side-chain functions of the serine and lysine are in contact with one another. Three independent methods were used in this report to address the question of the protonation state of this important lysine (Lys-73) in the TEM-1 ␤-lactamase from Escherichia coli. These techniques included perturbation of the pK a of Lys-73 by the study of the ␥-thialysine-73 variant and the attendant kinetic analyses, investigation of the protonation state by titration of specifically labeled proteins by nuclear magnetic resonance, and by computational treatment using the thermodynamic integration method. All three methods indicated that the pK a of Lys-73 of this enzyme is attenuated to 8.0 -8.5. It is argued herein that the unique ground-state ion pair of Glu-166 and Lys-73 of class A ␤-lactamases has actually raised the pK a of the active site lysine to 8.0 -8.5 from that of the parental penicillin-binding protein. Whereas we cannot rule out that Glu-166 might activate the active site water, which in turn promotes Ser-70 for the acylation event, such as proposed earlier, we would like to propose as a plausible alternative for the acylation step the possibility that the ion pair would reconfigure to the protonated Glu-166 and unprotonated Lys-73. As such, unprotonated Lys-73 could promote serine for acylation, a process that should be shared among all active-site serine ␤-lactamases and penicillin-binding proteins.A number of enzymes have evolved a catalytic strategy that depends on a transient acylation of an active site serine. The catalytic serine residue in these enzymes is followed by a lysine three residues toward the carboxyl termini of the proteins (i.e. . . . Ser-X-X-Lys . . . ). This sequence motif is seen in serinedependent ␤-lactamases and penicillin-binding proteins (PBPs 1 ), of which several hundred members are known. The catalytic implication of this Ser-X-X-Lys sequence motif for ␤-lactamases is debated in the literature, but the role of these residues in catalysis is likely to be general for the large group of proteins that share this sequence.␤-Lactamases are bacterial resistance enzymes to ␤-lactam antibiotics, which include penicillins and cephalosporins. Members of the class A ␤-lactamases are the most common among pathogenic bacteria. These enzymes undergo acylation and deacylation at Ser-70 during substrate turnover (1, 2). The process of deacylation of the acyl-enzyme intermediate is best understood. Glu-166 is the active-site general base that promotes a water molecule in the deacylation step (3-5). On the other hand, how the active-site serine experiences ...

show abstract

Section: Resultsmentioning

confidence: 99%

The Importance of a Critical Protonation State and the Fate of the Catalytic Steps in Class A β-Lactamases and Penicillin-binding Proteins

Golemi-Kotra

Meroueh

Kim

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Several of the clinical protease inhibitors were designed with the aid of molecular mechanics calculations, such as indinavir [35], and amprenavir [36]. The structural flexibility and opening of the protease flaps during the binding of an inhibitor have been studied by molecular dynamics [37][38][39][40].…”

Section: Molecular Mechanics Models and Simula-tionsmentioning

confidence: 99%

Structure Based Drug Design for HIV Protease: From Molecular Modeling to Cheminformatics

Volarath

Harrison²,

Weber³

2007

CTMC

View full text Add to dashboard Cite

Significant progress over the past decade in virtual representations of molecules and their physicochemical properties has produced new drugs from virtual screening of the structures of single protein molecules by conventional modeling methods. The development of clinical antiviral drugs from structural data for HIV protease has been a major success in structure based drug design. Techniques for virtual screening involve the ranking of the affinity of potential ligands for the target site on a protein. Two main alternatives have been developed: modeling of the target protein with a series of related ligand molecules, and docking molecules from a database to the target protein site. The computational speed and prediction accuracy will depend on the representation of the molecular structure and chemistry, the search or simulation algorithm, and the scoring function to rank the ligands. Moreover, the general challenges in modern computational drug design arise from the profusion of data, including whole genomes of DNA, protein structures, chemical libraries, affinity and pharmacological data. Therefore, software tools are being developed to manage and integrate diverse data, and extract and visualize meaningful relationships. Current areas of research include the development of searchable chemical databases, which requires new algorithms to represent molecules and search for structurally or chemically similar molecules, and the incorporation of machine learning techniques for data mining to improve the accuracy of predictions. Examples will be presented for the virtual screening of drugs that target HIV protease.

show abstract

“…A structure-assisted drug design effort by Murcko and coworkers including FEP calculations contributed towards the discovery of the FDA-approved PR inhibitor amprenavir (formerly VX-478) [83–85]. Additional successful applications of the FEP method for the calculation of HIV-1 PR inhibition, including non-peptide inhibitors, have been reported by McCarrick and Kollman [86], Rao and Murcko [87], Varney et al .…”

Section: Development Of Hiv-1 Inhibitors Guided By Fep Calculationsmentioning

confidence: 99%

Identification of HIV Inhibitors Guided by Free Energy Perturbation Calculations

Acevedo¹,

Ambrose²,

Flaherty³

et al. 2012

CPD

View full text Add to dashboard Cite

Free energy perturbation (FEP) theory coupled to molecular dynamics (MD) or Monte Carlo (MC) statistical mechanics offers a theoretically precise method for determining the free energy differences of related biological inhibitors. Traditionally requiring extensive computational resources and expertise, it is only recently that its impact is being felt in drug discovery. A review of computer-aided anti-HIV efforts employing FEP calculations is provided here that describes early and recent successes in the design of human immunodeficiency virus type 1 (HIV-1) protease and non-nucleoside reverse transcriptase inhibitors. In addition, our ongoing work developing and optimizing leads for small molecule inhibitors of cyclophilin A (CypA) is highlighted as an update on the current capabilities of the field. CypA has been shown to aid HIV-1 replication by catalyzing the cis/trans isomerization of a conserved Gly-Pro motif in the N-terminal domain of HIV-1 capsid (CA) protein. In the absence of a functional CypA, e.g., by the addition of an inhibitor such as cyclosporine A (CsA), HIV-1 has reduced infectivity. Our simulations of acylurea-based and 1-indanylketone-based CypA inhibitors have determined that their nanomolar and micromolar binding affinities, respectively, are tied to their ability to stabilize Arg55 and Asn102. A structurally novel 1-(2,6-dichlorobenzamido) indole core was proposed to maximize these interactions. FEP-guided optimization, experimental synthesis, and biological testing of lead compounds for toxicity and inhibition of wild-type HIV-1 and CA mutants have demonstrated a dose-dependent inhibition of HIV-1 infection in two cell lines. While the inhibition is modest compared to CsA, the results are encouraging.

show abstract

Calculation of solvation and binding free energy differences between VX-478 and its analogs by free energy perturbation and AMSOL methods

Cited by 31 publications

References 24 publications

The Importance of a Critical Protonation State and the Fate of the Catalytic Steps in Class A β-Lactamases and Penicillin-binding Proteins

The Importance of a Critical Protonation State and the Fate of the Catalytic Steps in Class A β-Lactamases and Penicillin-binding Proteins

Structure Based Drug Design for HIV Protease: From Molecular Modeling to Cheminformatics

Identification of HIV Inhibitors Guided by Free Energy Perturbation Calculations

Contact Info

Product

Resources

About