Article ; Online: Study of SQ109 analogs binding to mycobacterium MmpL3 transporter using MD simulations and alchemical relative binding free energy calculations.
Journal of computer-aided molecular design
2023 Volume 37, Issue 5-6, Page(s) 245–264
Abstract: N-geranyl-N΄-(2-adamantyl)ethane-1,2-diamine (SQ109) is a tuberculosis drug that has high potency against Mycobacterium tuberculosis (Mtb) and may function by blocking cell wall biosynthesis. After the crystal structure of MmpL3 from Mycobacterium ... ...
| Abstract | N-geranyl-N΄-(2-adamantyl)ethane-1,2-diamine (SQ109) is a tuberculosis drug that has high potency against Mycobacterium tuberculosis (Mtb) and may function by blocking cell wall biosynthesis. After the crystal structure of MmpL3 from Mycobacterium smegmatis in complex with SQ109 became available, it was suggested that SQ109 inhibits Mmpl3 mycolic acid transporter. Here, we showed using molecular dynamics (MD) simulations that the binding profile of nine SQ109 analogs with inhibitory potency against Mtb and alkyl or aryl adducts at C-2 or C-1 adamantyl carbon to MmpL3 was consistent with the X-ray structure of MmpL3 - SQ109 complex. We showed that rotation of SQ109 around carbon-carbon bond in the monoprotonated ethylenediamine unit favors two gauche conformations as minima in water and lipophilic solvent using DFT calculations as well as inside the transporter's binding area using MD simulations. The binding assays in micelles suggested that the binding affinity of the SQ109 analogs was increased for the larger, more hydrophobic adducts, which was consistent with our results from MD simulations of the SQ109 analogues suggesting that sizeable C-2 adamantyl adducts of SQ109 can fill a lipophilic region between Y257, Y646, F260 and F649 in MmpL3. This was confirmed quantitatively by our calculations of the relative binding free energies using the thermodynamic integration coupled with MD simulations method with a mean assigned error of 0.74 kcal mol |
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| MeSH term(s) | Antitubercular Agents/pharmacology ; Molecular Dynamics Simulation ; Bacterial Proteins/chemistry ; Membrane Transport Proteins/chemistry ; Membrane Transport Proteins/metabolism ; Mycobacterium tuberculosis ; Ethylenediamines/metabolism ; Ethylenediamines/pharmacology |
| Chemical Substances | Antitubercular Agents ; Bacterial Proteins ; Membrane Transport Proteins ; N-geranyl-N'-(2-adamantyl)ethane-1,2-diamine ; Ethylenediamines |
| Language | English |
| Publishing date | 2023-05-02 |
| Publishing country | Netherlands |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ZDB-ID | 808166-9 |
| ISSN | 1573-4951 ; 0920-654X |
| ISSN (online) | 1573-4951 |
| ISSN | 0920-654X |
| DOI | 10.1007/s10822-023-00504-6 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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