Toward the Discovery of a Novel Class of Leads for High Altitude Disorders by Virtual Screening and Molecular Dynamics Approaches Targeting Carbonic Anhydrase

International Journal of Molecular Sciences

卷:23

Faizul Azam¹  Mohamed Jawed Ahsan²  Mohammad Akhlaquer Rahman³  Musarrat Husain Warsi³  Abuzer Ali⁴  Amena Ali⁵ 

[1] Department of Pharmaceutical Chemistry & Pharmacognosy, Unaizah College of Pharmacy, Qassim University, Unaizah 51911, Saudi Arabia;

[2] Department of Pharmaceutical Chemistry, Maharishi Arvind College of Pharmacy, Jaipur, Rajasthan 302 039, India;

[3] Department of Pharmaceutics and Industrial Pharmacy, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia;

[4] Department of Pharmacognosy, College of Pharmacy, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia;

[5] High Altitude Research Center, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia;

关键词: high-altitude disorders;    carbonic anhydrase;    virtual screening;    molecular dynamics;    DFT;   

DOI  :  10.3390/ijms23095054

来源: DOAJ

【 摘 要 】

For decades, carbonic anhydrase (CA) inhibitors, most notably the acetazolamide-bearing 1,3,4-thiadiazole moiety, have been exploited at high altitudes to alleviate acute mountain sickness, a syndrome of symptomatic sensitivity to the altitude characterized by nausea, lethargy, headache, anorexia, and inadequate sleep. Therefore, inhibition of CA may be a promising therapeutic strategy for high-altitude disorders. In this study, co-crystallized inhibitors with 1,3,4-thiadiazole, 1,3-benzothiazole, and 1,2,5-oxadiazole scaffolds were employed for pharmacophore-based virtual screening of the ZINC database, followed by molecular docking and molecular dynamics simulation studies against CA to find possible ligands that may emerge as promising inhibitors. Compared to the co-crystal ligands of PDB-1YDB, 6BCC, and 6IC2, ZINC12336992, ZINC24751284, and ZINC58324738 had the highest docking scores of −9.0, −9.0, and −8.9 kcal/mol, respectively. A molecular dynamics (MD) simulation analysis of 100 ns was conducted to verify the interactions of the top-scoring molecules with CA. The system’s backbone revealed minor fluctuations, indicating that the CA–ligand complex was stable during the simulation period. Simulated trajectories were used for the MM-GBSA analysis, showing free binding energies of −16.00 ± 0.19, −21.04 ± 0.17, and −19.70 ± 0.18 kcal/mol, respectively. In addition, study of the frontier molecular orbitals of these compounds by DFT-based optimization at the level of B3LYP and the 6-311G(d,p) basis set showed negative values of the HOMO and LUMO, indicating that the ligands are energetically stable, which is essential for forming a stable ligand–protein complex. These molecules may prove to be a promising therapy for high-altitude disorders, necessitating further investigations.

【 授权许可】

Unknown