MM/GBSA prediction of relative binding affinities of carbonic anhydrase inhibitors: effect of atomic charges and comparison with Autodock4Zn

Abstract

Carbonic anhydrase is an attractive drug target for the treatment of many diseases. This paper examines the ability of end-state MM/GBSA methods to rank inhibitors of carbonic anhydrase in terms of their binding affinities. The MM/GBSA binding energies were evaluated using different atomic charge schemes (Mulliken, ESP and NPA) at different levels of theories, including Hartree–Fock, B3LYP-D3(BJ), and M06-2X with the 6–31G(d,p) basis set. For a large test set of 32 diverse inhibitors, the use of B3LYP-D3(BJ) ESP atomic charges yielded the strongest correlation with experiment (R2 = 0.77). The use of the recently enhanced Autodock Vina and zinc optimised AD4Zn force field also predicted ligand binding affinities with moderately strong correlation (R2 = 0.64) at significantly lower computational cost. However, the docked poses deviate significantly from crystal structures. Overall, this study demonstrates the applicability of docking to estimate ligand binding affinities for a diverse range of CA inhibitors, and indicates that more theoretically robust MM/GBSA simulations show promise for improving the accuracy of predicted binding affinities, as long as a validated set of parameters is used. Graphical abstract

Identification and Validation of Compounds Targeting Leishmania major Leucyl-Aminopeptidase M17

“…The predicted poses for the inhibitors were further validated through binding free energy calculations using the MM/GBSA method. 27 Essentially, a higher effective binding free energy is predicted for DDD00057570 (ΔH b MM/GBSA = −26.2 kcal/mol) compared with that of DDD00097924 (ΔH b MM/GBSA = −24.1 kcal/mol), in agreement with the lower IC 50 observed for the first inhibitor (Figure 2). In addition, the calculated relative binding free energy…”

“…The predicted poses for the inhibitors were further validated through binding free energy calculations using the MM/GBSA method. 27 Essentially, a higher effective binding free energy is predicted for DDD00057570 (Δ H b MM/GBSA = −26.2 kcal/mol) compared with that of DDD00097924 (Δ H b MM/GBSA = −24.1 kcal/mol), in agreement with the lower IC 50 observed for the first inhibitor ( Figure 2 ). In addition, the calculated relative binding free energy (ΔΔ G = Δ H b MM/GBSA [DDD00097924] - Δ H b MM/GBSA [DDD00057570]) between these two compounds of 2.1 kcal/mol differs in less than 1 kcal/mol from the experimental ΔΔ G of 1.3 kcal/mol, validating the docking predictions.…”

“…(D) Lineweaver–Burk plot for the diagnosis of the modality of r Lm LAP inhibition by DDD00097924 under the same conditions as for DDD00057570. Δ H b MM/GBSA : effective binding free energy by the MM/GBSA method …”

In Silico, Preparation and in Vitro Studies of Benzylidene-Based Hydroxy Benzyl Urea Derivatives as Free Radical Scavengers in Parkinson’s Disease

“…Furthermore, the parameters Gcovalent, Gcouloumb, and GvdW were determined using the Schrodinger suite 2022's MM-GBSA module. The compound HBU-2 was found to have the highest docking score of-9.699 kcal/mol with an MM-GBSA binding energy of-49.184 among all the designed derivatives, whereas having negative energy visualized favorable binding energy towards the protein [20]. The ΔGcovalent for the compound HBU-2 was found to be 8.56.…”

In silico evaluation of a new compound incorporating 4(3H)-quinazolinone and sulfonamide as a potential inhibitor of a human carbonic anhydrase

“…In search of competitive inhibitors of hCA-II, Yazg Dizdaroglu and others designed and evaluated a number of pyrazole compounds as carbonic anhydrase inhibitors using a molecular modelling approach [ 23 ]. Another investigation on the inhibition effect of carbonic anhydrase was carried out by Mackenzie Taylor and Junming, who employed computational methodologies to predict relative binding affinities for a set of structurally differing ligands [ 24 ].…”