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

Abstract

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.

Dependence on linkers’ flexibility designed for benzenesulfonamides targeting discovery of novel hCA IX inhibitors as potent anticancer agents

“…When ligands are bound, the R g can be utilised to monitor the folding and unfolding of protein structures. 69 Generally, the R g values for the drug-bound complexes were nearer to the native unbound hCA IX (Figure S10). The average R g values for compound 5d and hCA IX were measured to be 1.74–1.80 nm.…”

“…The molecular mechanics/Poisson Boltzmann surface area (MM/PBSA) approach was chosen for rescoring complexes because it computes the free energy of binding more quickly than other force field-based methods like the free energy perturbation (FEP) or thermodynamic integration (TI) methods. 69 The MM/PBSA calculation was performed using g_mmpbsa software. The calculated binding free energies are illustrated in Table 9 .…”

Progress of Section “Biochemistry” in 2022

“…A relevant number of papers dealing with this enzyme, its inhibitors, activators and involvement in various diseases have been published in 2022 in this journal [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. The first group of contributed materials dealt with the use of this protein for investigations of basic biochemical approaches, such as protein folding [ 7 ], thermodynamic parameters assessment for protein–ligand interactions [ 8 ], bioluminescence resonance energy transfer connected to the binding of the metal ion to apoenzymes [ 9 ], the possibility to evidence chalcogen bonds in the X-ray crystal structures of CA–lig and adduct [ 10 ].…”

“…A large number of CA-related papers dealt with the drug design of CA inhibitors (CAIs) with various applications as anticancer agents (both for treatment and imaging) [ 13 , 14 , 15 , 16 , 17 , 18 , 19 ], antineuropathic pain compounds [ 20 ], mountain sickness leads [ 21 ], antiglaucoma agents [ 22 ] or antibacterials with a novel mechanism of action which, unlike classical antibiotics, target bacterial CAs from various pathogens [ 23 , 24 , 25 ]. Both sulfonamide and non-sulfonamide compounds have been reported in these interesting papers, which highly enrich the number of such pharmacological agents useful for the management of a multitude of pathological conditions [ 2 , 3 ].…”

Applications of machine learning in computer-aided drug discovery

“…In a recent study, MolAICal was employed to calculate the molecular synthetic accessibility score of traditional Chinese medicines in attempts to inhibit the SARS-CoV-2 nucleocapsid protein (Chen et al, 2022). In another application, MolAICal was utilized to calculate the relative binding energy of compounds from the ZINC database to inhibit carbonic anhydrase as a treatment for altitude sickness (Ali et al, 2022).…”