Testing automatic methods to predict free binding energy of host–guest complexes in SAMPL7 challenge

Serillon, Dylan; Bó, Carles; Barril, Xavier

doi:10.1007/s10822-020-00370-6

Cited by 13 publications

(11 citation statements)

References 46 publications

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“…In protein–ligand docking, the conformations of ligands binding to receptor proteins were assessed, and the binding energies between protein–ligand pairs were quantified. Whenever a ligand interacts with a protein, electrons are involved in the formation of covalent or noncovalent bonds [ 55 , 56 , 57 ]. These pi-alkyl and pi-sulfur interactions belong to the broad category of noncovalent interactions [ 58 ].…”

Section: Discussionmentioning

confidence: 99%

In Silico Evaluation of Iranian Medicinal Plant Phytoconstituents as Inhibitors against Main Protease and the Receptor-Binding Domain of SARS-CoV-2

et al. 2021

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The novel coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which initially appeared in Wuhan, China, in December 2019. Elderly individuals and those with comorbid conditions may be more vulnerable to this disease. Consequently, several research laboratories continue to focus on developing drugs to treat this infection because this disease has developed into a global pandemic with an extremely limited number of specific treatments available. Natural herbal remedies have long been used to treat illnesses in a variety of cultures. Modern medicine has achieved success due to the effectiveness of traditional medicines, which are derived from medicinal plants. The objective of this study was to determine whether components of natural origin from Iranian medicinal plants have an antiviral effect that can prevent humans from this coronavirus infection using the most reliable molecular docking method; in our case, we focused on the main protease (Mpro) and a receptor-binding domain (RBD). The results of molecular docking showed that among 169 molecules of natural origin from common Iranian medicinal plants, 20 molecules (chelidimerine, rutin, fumariline, catechin gallate, adlumidine, astragalin, somniferine, etc.) can be proposed as inhibitors against this coronavirus based on the binding free energy and type of interactions between these molecules and the studied proteins. Moreover, a molecular dynamics simulation study revealed that the chelidimerine–Mpro and somniferine–RBD complexes were stable for up to 50 ns below 0.5 nm. Our results provide valuable insights into this mechanism, which sheds light on future structure-based designs of high-potency inhibitors for SARS-CoV-2.

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Section: Discussionmentioning

confidence: 99%

In Silico Evaluation of Iranian Medicinal Plant Phytoconstituents as Inhibitors against Main Protease and the Receptor-Binding Domain of SARS-CoV-2

et al. 2021

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“…There are three variants of GFNn-xTB that are developed ( n = 0, 1, and 2), which differ in accuracy and efficiency. They have been successfully applied in the optimization of organometallic complexes, structure sampling, exploring the reaction profiles, and macromolecule structure optimization. − In addition, the electronic effects are still included at the semiempirical level of theory, which are challenging systems for the DFT method . The empirical FF parameters for the GFN2-xTB method are fitted to reproduce the results of DFT (B97-3c) .…”

Section: Experimental Sectionmentioning

confidence: 99%

N-Vinyl Caprolactam/Maleic-Based Copolymers as Kinetic Hydrate Inhibitors: The Effect of Internal Hydrogen Bonding

et al. 2022

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Kinetic hydrate inhibitors (KHIs) have been used for over 25 years to prevent gas hydrate formation in oil and gas production flow lines, but they are some of the most expensive oilfield production chemicals. The main component in KHI formulations is a water-soluble polymer with many amphiphilic groups. Usually, in commercial KHI polymers, the hydrophilic part of these groups is the amide group. In addition, KHI polymers are often incompatible with film-forming corrosion inhibitors. Therefore, we sought to find cheaper but effective KHIs that could also act as a flow line corrosion inhibitor. Continuing earlier work from our group with maleic-based polymers, we have now explored maleic acid/N-vinyl caprolactam (MAcid/VCap) copolymers to introduce VCap, a well-known KHI monomer, together with the cheaper MA monomer. KHI performance screening tests were conducted under high pressure with a structure II-forming natural gas mixture in steel rocking cells using the slow (1 °C/h) constant-cooling test method. Surprisingly, the MAcid/VCap copolymer showed very poor KHI efficacy. GFN2-xTB molecular dynamics simulations revealed that MAcid/VCap exhibits intra-hydrogen bond networks that trap the polymer morphology in the globular form. In this scenario, the caprolactam ring is encapsulated inside the polymer structure due to the intra-hydrogen bonds and the hydrophobic interactions that minimize its ability to interact with the hydrate surfaces, which significantly reduces the MAcid/VCap kinetic inhibition performance. However, the polymer in such globular forms still displays an important amount of its carboxylic groups exposed to water, which explains the water solubility. In contrast to MAcid/VCap copolymers, maleimide derivatives with dibutylamino end groups were effective KHIs and even better with dibutylamine oxide end groups. A terpolymer of MA/VCap reacted with N,N-dibutylaminopropylamine followed by subsequent oxidation of the end groups to dibutylamine oxide and gave the best performance of any maleic-based polymer reported to date. The combination of caprolactam and dibutylamine oxide groups can be thought of as synergism within the same polymer, akin to the excellent synergy of the separate molecules, tributylamine oxide and PVCap.

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“…The TrimerTrip submissions included 3 ranked and 4 non-ranked, GDCCs included 4 ranked and 12 non-ranked, and CD-derivatives had 3 ranked and 6 non-ranked (Figure 5). For a large portion of methods submitted, docking was used to obtain starting structures, and one submission used self association molecular dynamics (SA-MD) [96]. General classical fixed charge force fields were commonly used, as has become common in SAMPL host-guest challenges (see Section 6.1.2 for methods submitted to SAMPL7 host-guest challenge).…”

Section: Resultsmentioning

confidence: 99%

“…and polarizable force fields (AMOEBA) [94], different charging schemes (AM1BCC [92,95], RESP [95]), several explicit water models (TIP3P [92], TIP4P-Ew [95], OPC [93]) and even implicit solvent [95]. Outside of simulation-based free energy methods, quantum mechanical (QM) and QM/MM (molecular mechanics) approaches were also used [95], and one group employed machine learning [96]. In addition, several groups submitted multiple predictions (particularly for the GDCCs) and the ensuing results are important to provide insight and give merit to the methods used here.…”

Section: Participant Calculation Methodologiesmentioning

confidence: 99%

“…Interestingly, all of the predictions within 2 kcal/mol used starting poses generated not by docking, but by using SA-MD. The SA-MD approach makes the assumption that the host is not in its proper conformation and the host and guest are allowed to associate on their own [43,96]. It would be interesting to see the predictive accuracy of this approach on the remaining TrimerTrip host-guest systems, and which systems if any prove to be troublesome.…”

Section: Trimertripmentioning

confidence: 99%

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SAMPL7 Host-Guest Challenge Overview: Assessing the reliability of polarizable and non-polarizable methods for binding free energy calculations

Amezcua¹,

Khoury²,

Mobley³

2020

Preprint

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The SAMPL challenges focus on testing and driving progress of computational methods to help guide pharmaceutical drug discovery. However, assessment of methods for predicting binding affinities is often hampered by computational challenges such as conformational sampling, protonation state uncertainties, variation in test sets selected, and even lack of high quality experimental data. SAMPL blind challenges have thus frequently included a component focusing on host-guest binding, which removes some of these challenges while still focusing on molecular recognition. Here, we report on the results of the SAMPL7 blind prediction challenge for host-guest affinity prediction. In this study, we focused on three different host-guest categories -- a familiar deep cavity cavitand series which has been featured in several prior challenges (where we examine binding of a series of guests to two hosts), a new series of cyclodextrin derivatives which are monofunctionalized around the rim to add amino acid-like functionality (where we examine binding of two guests to a series of hosts), and binding of a series of guests to a new acyclic TrimerTrip host which is related to previous cucurbituril hosts. Many predictions used methods based on molecular simulations, and overall success was mixed, though several methods stood out. As in SAMPL6, we find that one strategy for achieving reasonable accuracy here was to make empirical corrections to binding predictions based on previous data for host categories which have been studied well before, though this can be of limited value when new systems are included. Additionally, we found that alchemical free energy methods using the AMOEBA polarizable force field had considerable success for the two host categories in which they participated. The new TrimerTrip system was also found to introduce some sampling problems, because multiple conformations may be relevant to binding and interconvert only slowly. Overall, results in this challenge tentatively suggest that further investigation of polarizable force fields for these challenges may be warranted.

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Testing automatic methods to predict free binding energy of host–guest complexes in SAMPL7 challenge

Cited by 13 publications

References 46 publications

In Silico Evaluation of Iranian Medicinal Plant Phytoconstituents as Inhibitors against Main Protease and the Receptor-Binding Domain of SARS-CoV-2

In Silico Evaluation of Iranian Medicinal Plant Phytoconstituents as Inhibitors against Main Protease and the Receptor-Binding Domain of SARS-CoV-2

N-Vinyl Caprolactam/Maleic-Based Copolymers as Kinetic Hydrate Inhibitors: The Effect of Internal Hydrogen Bonding

SAMPL7 Host-Guest Challenge Overview: Assessing the reliability of polarizable and non-polarizable methods for binding free energy calculations

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