User-Friendly Quantum Mechanics: Applications for Drug Discovery

Kotev, Martin; Sarrat, Laurie; Gonzalez, Constantino Diaz

doi:10.1007/978-1-0716-0282-9_15

Cited by 13 publications

(4 citation statements)

References 155 publications

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“…However, special care will be needed to develop accurate and transferable force field parameters for the two photoswitch forms [ 141 ]. Quantum mechanics/molecular mechanics (QM/MM) MD [ 142 ], in combination with excited state methods, will also allow us to study the photoisomerization of the azobenzene group within the PCL or PTL, either in solution or bound to the target protein. Nonetheless, going from the previous studies of azobenzene in solution [ 143 , 144 ] to photoswitchable ligands in complex with their target protein is likely to require adjustments in the theoretical treatment of the photochromic group excited states, as well as to address possible super-heating effects due to photoexcitation.…”

Section: Conclusion and Perspectivesmentioning

confidence: 99%

Photopharmacology of Ion Channels through the Light of the Computational Microscope

Nin‐Hill

Mueller

Molteni

et al. 2021

IJMS

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The optical control and investigation of neuronal activity can be achieved and carried out with photoswitchable ligands. Such compounds are designed in a modular fashion, combining a known ligand of the target protein and a photochromic group, as well as an additional electrophilic group for tethered ligands. Such a design strategy can be optimized by including structural data. In addition to experimental structures, computational methods (such as homology modeling, molecular docking, molecular dynamics and enhanced sampling techniques) can provide structural insights to guide photoswitch design and to understand the observed light-regulated effects. This review discusses the application of such structure-based computational methods to photoswitchable ligands targeting voltage- and ligand-gated ion channels. Structural mapping may help identify residues near the ligand binding pocket amenable for mutagenesis and covalent attachment. Modeling of the target protein in a complex with the photoswitchable ligand can shed light on the different activities of the two photoswitch isomers and the effect of site-directed mutations on photoswitch binding, as well as ion channel subtype selectivity. The examples presented here show how the integration of computational modeling with experimental data can greatly facilitate photoswitchable ligand design and optimization. Recent advances in structural biology, both experimental and computational, are expected to further strengthen this rational photopharmacology approach.

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Section: Conclusion and Perspectivesmentioning

confidence: 99%

Photopharmacology of Ion Channels through the Light of the Computational Microscope

Nin‐Hill

Mueller

Molteni

et al. 2021

IJMS

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show abstract

“…Computational quantum chemistry provides a more accurate approach to describing molecular structures in drug design than classical force field-based molecular mechanics methods. QM calculations play a critical role for certain problems in the field, such as metal binding in metalloenzymes, reaction mechanism study, covalent inhibitor design 23 . Other applications of QM methods include calculation of molecular properties, QM-based descriptor for QSAR, parameterization of forcefields, and estimation of protein-ligand binding affinities [23][24][25][26] .…”

Section: Introductionmentioning

confidence: 99%

“…QM calculations play a critical role for certain problems in the field, such as metal binding in metalloenzymes, reaction mechanism study, covalent inhibitor design 23 . Other applications of QM methods include calculation of molecular properties, QM-based descriptor for QSAR, parameterization of forcefields, and estimation of protein-ligand binding affinities [23][24][25][26] . Major QM methods used in the field of computer-aided drug discovery (CADD) can be classified to semi-empirical QM methods, Hatree-Fock (HF), post-Hatree-Fock (pHF) methods, and density functional theory (DFT).…”

Section: Introductionmentioning

confidence: 99%

Quantum simulation of preferred tautomeric state prediction

Shee,

Yeh,

Hsiao

et al. 2023

npj Quantum Inf

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Prediction of tautomers plays an essential role in computer-aided drug discovery. However, it remains a challenging task nowadays to accurately predict the canonical tautomeric form of a given drug-like molecule. Lack of extensive tautomer databases, most likely due to the difficulty in experimental studies, hampers the development of effective empirical methods for tautomer predictions. A more accurate estimation of the stable tautomeric form can be achieved by quantum chemistry calculations. Yet, the computational cost required prevents quantum chemistry calculation as a standard tool for tautomer prediction in computer-aided drug discovery. In this paper we propose a hybrid quantum chemistry-quantum computation workflow to efficiently predict the dominant tautomeric form. Specifically, we select active-space molecular orbitals based on quantum chemistry methods. Then we utilize efficient encoding methods to map the Hamiltonian onto quantum devices to reduce the qubit resources and circuit depth. Finally, variational quantum eigensolver (VQE) algorithms are employed for ground state estimation where hardware-efficient ansatz circuits are used. To demonstrate the applicability of our methodology, we perform experiments on two tautomeric systems: acetone and Edaravone, each having 52 and 150 spin-orbitals in the Slater Type Orbital - 3 Gaussian (STO-3G) basis set, respectively. Our numerical results show that their tautomeric state prediction agrees with the Coupled Cluster Singles and Doubles (CCSD) benchmarks. Moreover, the required quantum resources are efficient: in the example of Edaravone, we could achieve chemical accuracy with only eight qubits and 80 two-qubit gates.

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“…Since the successful development of the HIV protease inhibitor nelfinavir in the USA in 1997, computational techniques have become a vital tool in drug discovery initiatives and a cornerstone for new drug development methodologies [11,12]. Recently, the fast rise of computational methods for drug discovery such as pharmacophore modeling, virtual screening, molecular dynamics, and quantum chemical computations has had a substantial and unprecedented influence on drug designs and yielded valuable insights into various therapeutic regimens [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

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

Ali

Warsi

et al. 2022

IJMS

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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.

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User-Friendly Quantum Mechanics: Applications for Drug Discovery

Cited by 13 publications

References 155 publications

Photopharmacology of Ion Channels through the Light of the Computational Microscope

Photopharmacology of Ion Channels through the Light of the Computational Microscope

Quantum simulation of preferred tautomeric state prediction

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

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