Computational chemical biology and drug design: Facilitating protein structure, function, and modulation studies

Zheng, Mingyue; Zhao, Jihui; Chen, Cui; Fu, Zunyun; Li, Xutong; Liu, Xiaohong; Ding, Xiaoyu; Tan, Xin; Li, Fēi; Luo, Xiaomin; Chen, Kaixian; Jiang, Hualiang

doi:10.1002/med.21483

Cited by 47 publications

(27 citation statements)

References 287 publications

(533 reference statements)

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“…More specifically, drug design that relies on the knowledge of the three-dimensional structure of the biomolecular target is known as structure-based drug design. In order to generate this type of drug design, an increasingly important number of computational methods for improving the affinity, selectivity and stability of these protein-based therapeutics have also been developed [ 14 , 15 , 16 ].…”

Section: Discussionmentioning

confidence: 99%

Homology Model and Docking-Based Virtual Screening for Ligands of Human Dyskerin as New Inhibitors of Telomerase for Cancer Treatment

Armando

Gómez

Juritz

et al. 2018

IJMS

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Immortality is one of the main features of cancer cells. Tumor cells have an unlimited replicative potential, principally due to the holoenzyme telomerase. Telomerase is composed mainly by dyskerin (DKC1), a catalytic retrotranscriptase (hTERT) and an RNA template (hTR). The aim of this work is to develop new inhibitors of telomerase, selecting the interaction between hTR–DKC1 as a target. We designed two models of the human protein DKC1: homology and ab initio. These models were evaluated by different procedures, revealing that the homology model parameters were the most accurate. We selected two hydrophobic pockets contained in the PUA (pseudouridine synthase and archaeosine transglycosylase) domain, using structural and stability analysis. We carried out a docking-based virtual screen on these pockets, using the reported mutation K314 as the center of the docking. The hDKC1 model was tested against a library of 450,000 drug-like molecules. We selected the first 10 molecules that showed the highest affinity values to test their inhibitory activity on the cell line MDA MB 231 (Monroe Dunaway Anderson Metastasis Breast cancer 231), obtaining three compounds that showed inhibitory effect. These results allowed us to validate our design and set the basis to continue with the study of telomerase inhibitors for cancer treatment.

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Section: Discussionmentioning

confidence: 99%

Homology Model and Docking-Based Virtual Screening for Ligands of Human Dyskerin as New Inhibitors of Telomerase for Cancer Treatment

Armando

Gómez

Juritz

et al. 2018

IJMS

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“…Nevertheless, computational resources can be applied to other areas of knowledge, such as in forensic analyses [65], pharmacokinetics parameter predictions (absorption, distribution, metabolism, excretion, and toxicity) [66], binding kinetics predictions (k on and K off ) [67], understanding the role of water molecules [68], binding site predictions (orthosteric, allosteric, and hotspots) [69], compound optimization [70], and the creation of new synthetic pathways [71].…”

Section: The In Silico Approach: Putative Applications and Disadvantagesmentioning

confidence: 99%

A Brief View of Molecular Modeling Approaches to P2 Receptors

Alberto¹,

Santos²,

Ferreira³

et al. 2020

Receptors P1 and P2 as Targets for Drug Therapy in Humans

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Purinergic receptors are a class of receptors distributed into two groups, P1 and P2. P1 receptors are activated by nucleosides, like adenosine, while nucleotides active P2 receptors. In turn, P2 receptors comprise two families, metabotropic P2Y and ionotropic P2X. P2Y receptors consist in eight members, namely, P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14, described in mammals, while P2X includes seven members, numbered P2X1 to P2X7. These receptors have been described as expressed in practically all cells studied to date. In this context, P2 receptors are suggested as participating in certain diseases. The general approach applied in the discovery of new drugs is expensive and lengthy. Alternatively, in the last 20 years, molecular modeling has emerged as an exciting tool for the design of new drugs, in less time and at low costs. These tools allow for in silico testing of thousands of molecules against a target protein, as well as toxicity, absorption, distribution, metabolism, and constant affinity predictions of a given interaction. Thus, molecular modeling algorithms emerge as an increasingly important tool for the design of drugs targeting purinergic receptors as therapeutic targets of many diseases, including cancer, pain, inflammation, cardiovascular, and endocrine conditions.

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“…Advances in computational hardware also have facilitated the study of complex biological systems. In the last decade, molecular simulations of biological systems with millions of interacting particles over microsecond to millisecond timescales have been reported [64,91,92,93,94,95,96,97,98,99,100,101,102,103,104,105,106,107,108,109,110,111,112,113,114,115,116]. These simulations provide unprecedented insights into the system under investigation and bridge nanoscale data to macroscale experimental results.…”

Section: Need For Computational Modelingmentioning

confidence: 99%

Computational Nanoscopy of Tight Junctions at the Blood–Brain Barrier Interface

Rajagopal

Irudayanathan

Nangia

2019

IJMS

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The selectivity of the blood–brain barrier (BBB) is primarily maintained by tight junctions (TJs), which act as gatekeepers of the paracellular space by blocking blood-borne toxins, drugs, and pathogens from entering the brain. The BBB presents a significant challenge in designing neurotherapeutics, so a comprehensive understanding of the TJ architecture can aid in the design of novel therapeutics. Unraveling the intricacies of TJs with conventional experimental techniques alone is challenging, but recently developed computational tools can provide a valuable molecular-level understanding of TJ architecture. We employed the computational methods toolkit to investigate claudin-5, a highly expressed TJ protein at the BBB interface. Our approach started with the prediction of claudin-5 structure, evaluation of stable dimer conformations and nanoscale assemblies, followed by the impact of lipid environments, and posttranslational modifications on these claudin-5 assemblies. These led to the study of TJ pores and barriers and finally understanding of ion and small molecule transport through the TJs. Some of these in silico, molecular-level findings, will need to be corroborated by future experiments. The resulting understanding can be advantageous towards the eventual goal of drug delivery across the BBB. This review provides key insights gleaned from a series of state-of-the-art nanoscale simulations (or computational nanoscopy studies) performed on the TJ architecture.

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Computational chemical biology and drug design: Facilitating protein structure, function, and modulation studies

Cited by 47 publications

References 287 publications

Homology Model and Docking-Based Virtual Screening for Ligands of Human Dyskerin as New Inhibitors of Telomerase for Cancer Treatment

Homology Model and Docking-Based Virtual Screening for Ligands of Human Dyskerin as New Inhibitors of Telomerase for Cancer Treatment

A Brief View of Molecular Modeling Approaches to P2 Receptors

Computational Nanoscopy of Tight Junctions at the Blood–Brain Barrier Interface

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