A Conserved Allosteric Site on Drug-Metabolizing CYPs: A Systematic Computational Assessment
Cytochrome P450 enzymes (CYPs) are the largest group of enzymes involved in human drug metabolism. Ligand tunnels connect their active site buried at the core of the membrane-anchored protein to the surrounding solvent environment. Recently, evidence of a superficial allosteric site, here denoted as...
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-12-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/22/24/13215 |
| _version_ | 1797503951751348224 |
|---|---|
| author | André Fischer Martin Smieško |
| author_facet | André Fischer Martin Smieško |
| author_sort | André Fischer |
| collection | DOAJ |
| description | Cytochrome P450 enzymes (CYPs) are the largest group of enzymes involved in human drug metabolism. Ligand tunnels connect their active site buried at the core of the membrane-anchored protein to the surrounding solvent environment. Recently, evidence of a superficial allosteric site, here denoted as hotspot 1 (H1), involved in the regulation of ligand access in a soluble prokaryotic CYP emerged. Here, we applied multi-scale computational modeling techniques to study the conservation and functionality of this allosteric site in the nine most relevant mammalian CYPs responsible for approximately 70% of drug metabolism. In total, we systematically analyzed over 44 <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">μ</mi></semantics></math></inline-formula>s of trajectories from conventional MD, cosolvent MD, and metadynamics simulations. Our bioinformatic analysis and simulations with organic probe molecules revealed the site to be well conserved in the CYP2 family with the exception of CYP2E1. In the presence of a ligand bound to the H1 site, we could observe an enlargement of a ligand tunnel in several members of the CYP2 family. Further, we could detect the facilitation of ligand translocation by H1 interactions with statistical significance in CYP2C8 and CYP2D6, even though all other enzymes except for CYP2C19, CYP2E1, and CYP3A4 presented a similar trend. As the detailed comprehension of ligand access and egress phenomena remains one of the most relevant challenges in the field, this work contributes to its elucidation and ultimately helps in estimating the selectivity of metabolic transformations using computational techniques. |
| first_indexed | 2024-03-10T03:57:43Z |
| format | Article |
| id | doaj.art-a2cfa5172be144ab99e1cd0b9fe597d6 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T03:57:43Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-a2cfa5172be144ab99e1cd0b9fe597d62023-11-23T08:42:56ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-12-0122241321510.3390/ijms222413215A Conserved Allosteric Site on Drug-Metabolizing CYPs: A Systematic Computational AssessmentAndré Fischer0Martin Smieško1Computational Pharmacy, Departement of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 61, 4056 Basel, SwitzerlandComputational Pharmacy, Departement of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 61, 4056 Basel, SwitzerlandCytochrome P450 enzymes (CYPs) are the largest group of enzymes involved in human drug metabolism. Ligand tunnels connect their active site buried at the core of the membrane-anchored protein to the surrounding solvent environment. Recently, evidence of a superficial allosteric site, here denoted as hotspot 1 (H1), involved in the regulation of ligand access in a soluble prokaryotic CYP emerged. Here, we applied multi-scale computational modeling techniques to study the conservation and functionality of this allosteric site in the nine most relevant mammalian CYPs responsible for approximately 70% of drug metabolism. In total, we systematically analyzed over 44 <inline-formula><math xmlns="http://www.w3.org/1998/Math/MathML" display="inline"><semantics><mi mathvariant="sans-serif">μ</mi></semantics></math></inline-formula>s of trajectories from conventional MD, cosolvent MD, and metadynamics simulations. Our bioinformatic analysis and simulations with organic probe molecules revealed the site to be well conserved in the CYP2 family with the exception of CYP2E1. In the presence of a ligand bound to the H1 site, we could observe an enlargement of a ligand tunnel in several members of the CYP2 family. Further, we could detect the facilitation of ligand translocation by H1 interactions with statistical significance in CYP2C8 and CYP2D6, even though all other enzymes except for CYP2C19, CYP2E1, and CYP3A4 presented a similar trend. As the detailed comprehension of ligand access and egress phenomena remains one of the most relevant challenges in the field, this work contributes to its elucidation and ultimately helps in estimating the selectivity of metabolic transformations using computational techniques.https://www.mdpi.com/1422-0067/22/24/13215Cytochrome P450CYPallostericligand accesstunnelmolecular dynamics |
| spellingShingle | André Fischer Martin Smieško A Conserved Allosteric Site on Drug-Metabolizing CYPs: A Systematic Computational Assessment International Journal of Molecular Sciences Cytochrome P450 CYP allosteric ligand access tunnel molecular dynamics |
| title | A Conserved Allosteric Site on Drug-Metabolizing CYPs: A Systematic Computational Assessment |
| title_full | A Conserved Allosteric Site on Drug-Metabolizing CYPs: A Systematic Computational Assessment |
| title_fullStr | A Conserved Allosteric Site on Drug-Metabolizing CYPs: A Systematic Computational Assessment |
| title_full_unstemmed | A Conserved Allosteric Site on Drug-Metabolizing CYPs: A Systematic Computational Assessment |
| title_short | A Conserved Allosteric Site on Drug-Metabolizing CYPs: A Systematic Computational Assessment |
| title_sort | conserved allosteric site on drug metabolizing cyps a systematic computational assessment |
| topic | Cytochrome P450 CYP allosteric ligand access tunnel molecular dynamics |
| url | https://www.mdpi.com/1422-0067/22/24/13215 |
| work_keys_str_mv | AT andrefischer aconservedallostericsiteondrugmetabolizingcypsasystematiccomputationalassessment AT martinsmiesko aconservedallostericsiteondrugmetabolizingcypsasystematiccomputationalassessment AT andrefischer conservedallostericsiteondrugmetabolizingcypsasystematiccomputationalassessment AT martinsmiesko conservedallostericsiteondrugmetabolizingcypsasystematiccomputationalassessment |