TY - JOUR
T1 - Exploring Natural Product Activity and Species Source Candidates for Hunting ABCB1 Transporter Inhibitors
T2 - An In Silico Drug Discovery Study
AU - Ibrahim, Mahmoud A.A.
AU - Abdeljawaad, Khlood A.A.
AU - Abdelrahman, Alaa H.M.
AU - Jaragh-Alhadad, Laila A.
AU - Oraby, Hesham Farouk
AU - Elkaeed, Eslam B.
AU - Mekhemer, Gamal A.H.
AU - Gabr, Gamal A.
AU - Shawky, Ahmed M.
AU - Sidhom, Peter A.
AU - Soliman, Mahmoud E.S.
AU - Moustafa, Mahmoud F.
AU - Paré, Paul W.
AU - Hegazy, Mohamed Elamir F.
N1 - Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/5/1
Y1 - 2022/5/1
N2 - The P-glycoprotein (P-gp/ABCB1) is responsible for a xenobiotic efflux pump that shackles intracellular drug accumulation. Additionally, it is included in the dud of considerable antiviral and anticancer chemotherapies because of the multidrug resistance (MDR) phenomenon. In the search for prospective anticancer drugs that inhibit the ABCB1 transporter, the Natural Product Activity and Species Source (NPASS) database, containing >35,000 molecules, was explored for identifying ABCB1 inhibitors. The performance of AutoDock4.2.6 software to anticipate ABCB1 docking score and pose was first assessed according to available experimental data. The docking scores of the NPASS molecules were predicted against the ABCB1 transporter. Molecular dynamics (MD) simulations were conducted for molecules with docking scores lower than taxol, a reference inhibitor, pursued by molecular mechanics-generalized Born surface area (MM-GBSA) binding energy estimations. On the basis of MM-GBSA calculations, five compounds revealed promising binding affinities as ABCB1 inhibitors with ∆Gbinding < −105.0 kcal/mol. The binding affinity and stability of the identified inhibitors were compared to the chemotherapeutic agent. Structural and energetical analyses unveiled great steadiness of the investigated inhibitors within the ABCB1 active site throughout 100 ns MD simulations. Conclusively, these findings point out that NPC104372, NPC475164, NPC2313, NPC197736, and NPC477344 hold guarantees as potential ABCB1 drug candidates and warrant further in vitro/in vivo tests.
AB - The P-glycoprotein (P-gp/ABCB1) is responsible for a xenobiotic efflux pump that shackles intracellular drug accumulation. Additionally, it is included in the dud of considerable antiviral and anticancer chemotherapies because of the multidrug resistance (MDR) phenomenon. In the search for prospective anticancer drugs that inhibit the ABCB1 transporter, the Natural Product Activity and Species Source (NPASS) database, containing >35,000 molecules, was explored for identifying ABCB1 inhibitors. The performance of AutoDock4.2.6 software to anticipate ABCB1 docking score and pose was first assessed according to available experimental data. The docking scores of the NPASS molecules were predicted against the ABCB1 transporter. Molecular dynamics (MD) simulations were conducted for molecules with docking scores lower than taxol, a reference inhibitor, pursued by molecular mechanics-generalized Born surface area (MM-GBSA) binding energy estimations. On the basis of MM-GBSA calculations, five compounds revealed promising binding affinities as ABCB1 inhibitors with ∆Gbinding < −105.0 kcal/mol. The binding affinity and stability of the identified inhibitors were compared to the chemotherapeutic agent. Structural and energetical analyses unveiled great steadiness of the investigated inhibitors within the ABCB1 active site throughout 100 ns MD simulations. Conclusively, these findings point out that NPC104372, NPC475164, NPC2313, NPC197736, and NPC477344 hold guarantees as potential ABCB1 drug candidates and warrant further in vitro/in vivo tests.
KW - ABCB1
KW - NPASS
KW - molecular docking
KW - molecular dynamics (MD) simulations
KW - multidrug resistance (MDR)
UR - http://www.scopus.com/inward/record.url?scp=85130325730&partnerID=8YFLogxK
U2 - 10.3390/molecules27103104
DO - 10.3390/molecules27103104
M3 - Article
AN - SCOPUS:85130325730
SN - 1420-3049
VL - 27
JO - Molecules
JF - Molecules
IS - 10
M1 - 3104
ER -