More is simpler: Decomposition of <scp>ligand‐binding</scp> affinity for proteins being disordered

Wang, Xiaohui; Chong, Bin; Sun, Zhaoxi; Ruan, Hao; Yang, Yingguang; Song, Pengbo; Liu, Zhirong

doi:10.1002/pro.4375

Cited by 6 publications

(1 citation statement)

References 55 publications

(101 reference statements)

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“…We have proposed that the underlying philosophy of EBDD for IDPs can be described as "multiple dominant conformational affinity," which means that a potential ligand should bind well to several dominant conformations. It is important to note that this strategy is significantly different from the approach of accessing the potential binding ability using the best 171,172 or average 198 docking score. On one hand, an IDP ligand generally interacts with numerous conformations, not just with the best scoring conformation.…”

Section: Accidental Discoverymentioning

confidence: 99%

Rational drug design targeting intrinsically disordered proteins

Wang,

Xiong,

Lai

2023

WIREs Comput Mol Sci

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Intrinsically disordered proteins (IDPs) are proteins that perform important biological functions without well‐defined structures under physiological conditions. IDPs can form fuzzy complexes with other molecules, participate in the formation of membraneless organelles, and function as hubs in protein–protein interaction networks. The malfunction of IDPs causes major human diseases. However, drug design targeting IDPs remains challenging due to their highly dynamic structures and fuzzy interactions. Turning IDPs into druggable targets provides a great opportunity to extend the druggable target‐space for novel drug discovery. Integrative structural biology approaches that combine information derived from computational simulations, artificial intelligence/data‐driven analysis and experimental studies have been used to uncover the dynamic structures and interactions of IDPs. An increasing number of ligands that directly bind IDPs have been found either by target‐based experimental and computational screening or phenotypic screening. Along with the understanding of IDP binding with its partners, structure‐based drug design strategies, especially conformational ensemble‐based computational ligand screening and computer‐aided ligand optimization algorithms, have greatly accelerated the development of IDP ligands. It is inspiring that several IDP‐targeting small‐molecule and peptide drugs have advanced into clinical trials. However, new computational methods need to be further developed for efficiently discovering and optimizing specific and potent ligands for the vast number of IDPs. Along with the understanding of their dynamic structures and interactions, IDPs are expected to become valuable treasure of drug targets.This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics

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Section: Accidental Discoverymentioning

confidence: 99%

Rational drug design targeting intrinsically disordered proteins

Wang,

Xiong,

Lai

2023

WIREs Comput Mol Sci

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Comprehensive evaluation of end-point free energy techniques in carboxylated-pillar[6]arene host–guest binding: I. Standard procedure

Liu

Zheng

Qin

et al. 2022

J Comput Aided Mol Des

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Comprehensive evaluation of end-point free energy techniques in carboxylated-pillar[6]arene host–guest binding: II. regression and dielectric constant

Liu

Zheng

Cong

et al. 2022

J Comput Aided Mol Des

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End-point free energy calculations as a powerful tool have been widely applied in protein-ligand and protein-protein interactions. It is often recognized that these end-point techniques serve as an option of intermediate accuracy and computational cost compared with more rigorous statistical mechanic models (e.g., alchemical transformation) and coarser molecular docking. However, it is observed that this intermediate level of accuracy does not hold in relatively simple and prototypical host-guest systems. Specifically, in our previous work investigating a set of carboxylated-pillar[6]arene host-guest complexes, end-point methods provide free energy estimates deviating significantly from the experimental reference, and the rank of binding affinities is also incorrectly computed. These observations suggest the unsuitability and inapplicability of standard end-point free energy techniques in host-guest systems, and alteration and 2 / 41 development are required to make them practically usable. In this work, we consider two ways to improve the performance of end-point techniques. The first one is the PBSA_E regression that varies the weights of different free energy terms in the end-point calculation procedure, while the second one is considering the interior dielectric constant as an additional variable in the end-point equation. By detailed investigation of the calculation procedure and the simulation outcome, we prove that these two treatments (i.e., regression and dielectric constant) are manipulating the end-point equation in a somehow similar way, i.e., weakening the electrostatic contribution and strengthening the non-polar terms, although there are still many detailed differences between these two methods. With the trained end-point scheme, the RMSE of the computed affinities is improved from the standard ~12 kcal/mol to ~2.4 kcal/mol, which is comparable to another altered end-point method (ELIE) trained with system-specific data. This phenomenon along with the extremely efficient optimized-structure computation procedure suggests the regression (i.e., PBSA_E as well as its GBSA_E extension) as a practically applicable solution that brings end-point methods back into the library of usable tools for host-guest binding. However, the dielectric-constant-variable scheme cannot effectively minimize the experiment-calculation discrepancy for absolute binding affinities, but is able to improve the calculation of affinity ranks. This phenomenon is somehow different from the protein-ligand case and suggests the difference between host-guest and biomacromolecular (protein-ligand and proteinprotein) cases. Therefore, the spectrum of tools usable in protein-ligand cases could be unsuitable for hostguest binding, and numerical validations are necessary to screen out really workable solutions in these 'prototypical' situations.

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More is simpler: Decomposition of ligand‐binding affinity for proteins being disordered

Cited by 6 publications

References 55 publications

Rational drug design targeting intrinsically disordered proteins

Rational drug design targeting intrinsically disordered proteins

Comprehensive evaluation of end-point free energy techniques in carboxylated-pillar[6]arene host–guest binding: I. Standard procedure

Comprehensive evaluation of end-point free energy techniques in carboxylated-pillar[6]arene host–guest binding: II. regression and dielectric constant

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