Investigation of structural analogs of hydroxychloroquine for SARS-CoV-2 main protease (Mpro): A computational drug discovery study

Abstract

The main protease (Mpro) is the key enzyme of nCOVID-19 and plays a decisive role that makes it an attractive drug target. Multiple analysis of crystal structures reveal the presence of W1, W2, and W3 water locations in the active site pocket of Mpro; W1 and W2 are unstable and are weakly bonded with protein in comparison to W3 of Mpro-native. So, we adopt the water displacement method to occupy W1 or W2 sites by triggering HCQ or its analogs to inactivate the enzyme. Virtual screening is employed to find out best analogs of HCQ, molecular docking is used for water displacement from catalytic region of Mpro, and finally, MD simulations are conducted for validation of these findings. The docking study reveals that W1 and W2 are occupied by respective atoms of ZINC28706440 whereas W2 by HCQ and indacaterol. Finally, MD results demonstrate (i) HCQ occupies W1 and W2 positions but its analogs (indacaterol and ZINC28706440) are inadequate to retain either W1 or W2 (ii) His41 and Asp187 are stabilized by W3 in Mpro-native and His41, Cys145 and HCQ by W7 in ZINC28706440, and W4, W5, and W6 make water mediated bridge between indacaterol with His41. The structural, dynamical, and thermodynamic (WFP and J value) profiling parameters suggest that W3, W4, and W7 are prominent in their corresponding positions in comparison with W5 and W6. The final results conclude that ZINC28706440 may act as a best analog of HCQ with acceptable physico-chemical and toxicological scores and may further be synthesized for experimental validation.

A proteomics-MM/PBSA dual approach for the analysis of SARS-CoV-2 main protease substrate peptide specificity

“…Essentially, these methods evaluate the free binding energy of the ligand from MD simulation snapshots using energy terms of the MD force field, but approximating the polar energy terms with the Poisson-Boltzmann (PB) equation, estimating the non-polar energy terms using the solvent-accessible surface area (SASA) method and roughly approximating the entropic terms using normal-mode analysis. They have proven to be reliable methods for the computation of binding energy leading to numerous applications in small-molecule ligand binding and drug design [20] , [21] , [22] , protein-peptide interactions [23] , [24] , [25] , [26] , protein-protein interactions [27] , [28] and protein design [29] , [30] . Although their accuracy in some systems is in the order of 10 kJ/mol, both computational improvements in the calculation of individual terms of the binding energy as well as carrying out many short MD simulations [31] , [32] has helped obtain more accurate estimations of binding energies up to the 1 kJ/mol range.…”

Methodology-Centered Review of Molecular Modeling, Simulation, and Prediction of SARS-CoV-2

“…Cobicistat, flavin adenine dinucleotide, and simeprevir were suggested through drug ranking according to binding energy by MM/PB­(GB)­SA calculations. Other assessments based on docking and MM/PB­(GB)­SA calculations focused on specific drugs or compounds such as ravidasvir, lopinavir, ritonavir, saquinavir, teicoplanin, GC-376, calpain XII, calpain II, anti-HIV drugs, doxorubicin, chloroquine, quinoline, hydroxychloroquine, noscapine, echinocandins, coumarins, and their derivatives. − …”

Structural and thermodynamic properties of conserved water molecules in Mpro native: A combined approach by MD simulation and Grid Inhomogeneous Solvation Theory

“…[32][33][34][35][36] Few computational investigations have already been carried out to explore the role of water molecules at the catalytic region of the Mpro protein. 20,37 Experimental investigations for analyzing the importance of water molecules in the drug-binding process create challenges because collecting evidence from solvation effects on the ligand-binding zone and obtaining sufficiently detailed information about water solvation layers from crystal structures are complicated. 38,39 The crystallographically predicted water molecules are relevant for computational drug purposes if the water locations are predicted appropriately.…”

“…The role of water molecules from W1 to W3 was already discussed in our previous research work. 20,37 The inhomogeneous solvation theory allows us to identify the specific geometrical and electronic locations of water molecules in the DI and DII domains of the Mpro protein and compute their thermodynamic properties. 56 Multiple analyses of crystal structures of the native form of Mpro protein provide suggestions to identify the specific conserved water molecules in Mpro native and GIST-based energy profile will guide which conserved water molecules can be targeted to displace for water-based drug design.…”

“…56 Multiple analyses of crystal structures of the native form of Mpro protein provide suggestions to identify the specific conserved water molecules in Mpro native and GIST-based energy profile will guide which conserved water molecules can be targeted to displace for water-based drug design. 37,57,58 The medicinal chemistry methods explain that tightly bound and well-ordered water molecules may gain entropy and are difficult to replace by ligands. In contrast, weakly bound water molecules are primarily favorable for replacement by ligands that may expect to increase binding affinities.…”