Structural Basis and Computational Modeling of Chiral Drugs

Wang, Deping; Hu, Eric

doi:10.1002/9781118075647.ch7

Cited by 2 publications

(3 citation statements)

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“…Auf ein molekulares Modell und seinen schrittweisen Aufbau werden dabei drei Perspektiven angewandt: thermodynamische und elektrochemische Eigenschaften sowie die Berücksichtigung der räumlichen Anordnung eines Moleküls (ebd.). Dabei ist die molekulare Chiralität einer Verbindung und die daraus resultierende Anzahl von asymmetrischen Stereozentren und Enantiomeren neben anderen stereochemischen Spezifikationen von essentieller Bedeutung (Wang und Hu, 2011). Wie Prof. Ullmanns Verweis auf die molekulare Eigenschaft der Chiralität deutlich macht, lassen sich die Aktivitäten der Medizinalchemie beim Design kleiner Wirkstoffmoleküle ohne diese Eigenschaft nicht denken.…”

Section: Dr Albrechtsberger: Die Erzeugung Von Antikörpern (3) äHm Ge...unclassified

Chirale Welten

Lang¹

2021

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Section: Dr Albrechtsberger: Die Erzeugung Von Antikörpern (3) äHm Ge...unclassified

Chirale Welten

Lang¹

2021

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“…The therapeutic action of many chiral pharmaceutical compounds is dependent on the interaction of a single stereoisomer with a biological target . This includes statin drugs . Moreover, the presence of a noneffective stereoisomer can lead to unwanted side effects .…”

Section: Introductionmentioning

confidence: 99%

“… 1 This includes statin drugs. 2 Moreover, the presence of a noneffective stereoisomer can lead to unwanted side effects. 3 Accordingly, methods for the synthesis of stereochemically pure formulations are required for the production of pharmaceutically active ingredients.…”

Section: Introductionmentioning

confidence: 99%

Computation-Aided Engineering of Cytochrome P450 for the Production of Pravastatin

et al. 2022

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CYP105AS1 is a cytochrome P450 from Amycolatopsis orientalis that catalyzes monooxygenation of compactin to 6-epipravastatin. For fermentative production of the cholesterol-lowering drug pravastatin, the stereoselectivity of the enzyme needs to be inverted, which has been partially achieved by error-prone PCR mutagenesis and screening. In the current study, we report further optimization of the stereoselectivity by a computationally aided approach. Using the CoupledMoves protocol of Rosetta, a virtual library of mutants was designed to bind compactin in a propravastatin orientation. By examining the frequency of occurrence of beneficial substitutions and rational inspection of their interactions, a small set of eight mutants was predicted to show the desired selectivity and these variants were tested experimentally. The best CYP105AS1 variant gave >99% stereoselective hydroxylation of compactin to pravastatin, with complete elimination of the unwanted 6-epi-pravastatin diastereomer. The enzyme−substrate complexes were also examined by ultrashort molecular dynamics simulations of 50 × 100 ps and 5 × 22 ns, which revealed that the frequency of occurrence of near-attack conformations agreed with the experimentally observed stereoselectivity. These results show that a combination of computational methods and rational inspection could improve CYP105AS1 stereoselectivity beyond what was obtained by directed evolution. Moreover, the work lays out a general in silico framework for specificity engineering of enzymes of known structure.

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Structural Basis and Computational Modeling of Chiral Drugs

Cited by 2 publications

References 48 publications

Chirale Welten

Chirale Welten

Computation-Aided Engineering of Cytochrome P450 for the Production of Pravastatin

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