scholarly journals Machine intelligence design of 2019-nCoV drugs

2020 ◽  
Author(s):  
Kaifu Gao ◽  
Duc Duy Nguyen ◽  
Rui Wang ◽  
Guo-Wei Wei
Keyword(s):  
Binding Sites ◽  
Drug Target ◽  
Machine Intelligence ◽  
Respiratory Syndrome Virus ◽  
Viral Protease ◽  
Inhibitor Binding ◽  
Potential Effectiveness ◽  
Sequence Identity ◽  
Hiv Drugs ◽  
Network Complex

AbstractWuhan coronavirus, called 2019-nCoV, is a newly emerged virus that infected more than 9692 people and leads to more than 213 fatalities by January 30, 2020. Currently, there is no effective treatment for this epidemic. However, the viral protease of a coronavirus is well-known to be essential for its replication and thus is an effective drug target. Fortunately, the sequence identity of the 2019-nCoV protease and that of severe-acute respiratory syndrome virus (SARS-CoV) is as high as 96.1%. We show that the protease inhibitor binding sites of 2019-nCoV and SARS-CoV are almost identical, which means all potential anti-SARS-CoV chemotherapies are also potential 2019-nCoV drugs. Here, we report a family of potential 2019-nCoV drugs generated by a machine intelligence-based generative network complex (GNC). The potential effectiveness of treating 2019-nCoV by using some existing HIV drugs is also analyzed.

Inhibitor Binding Sites in the Protein Tyrosine Phosphatase SHP-2

2020 ◽  
Vol 20 (11) ◽  
pp. 1017-1030
Author(s):  
Haonan Zhang ◽  
Zhengquan Gao ◽  
Chunxiao Meng ◽  
Xiangqian Li ◽  
Dayong Shi
Keyword(s):  
Small Molecule ◽  
Protein Tyrosine Phosphatase ◽  
Binding Sites ◽  
Drug Target ◽  
Tyrosine Phosphatase ◽  
Cancer Drug ◽  
Cellular Activity ◽  
Binding Modes ◽  
Inhibitor Binding ◽  
Protein Tyrosine

Protein tyrosine phosphatase 2 (SHP-2) has long been proposed as a cancer drug target. Several small-molecule compounds with different mechanisms of SHP-2 inhibition have been reported, but none are commercially available. Pool selectivity over protein tyrosine phosphatase 1 (SHP-1) and a lack of cellular activity have hindered the development of selective SHP-2 inhibitors. In this review, we describe the binding modes of existing inhibitors and SHP-2 binding sites, summarize the characteristics of the sites involved in selectivity, and identify the suitable groups for interaction with the binding sites.

scholarly journals Precursors of Viral Proteases as Distinct Drug Targets

Viruses ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1981
Author(s):  
Taťána Majerová ◽  
Pavel Novotný
Keyword(s):  
Enzyme Activity ◽  
Host Cell ◽  
Binding Sites ◽  
Drug Target ◽  
Drug Targets ◽  
Mechanisms Of Action ◽  
Protease Domain ◽  
Viral Protease ◽  
Detailed Understanding ◽  
Viral Proteases

Viral proteases are indispensable for successful virion maturation, thus making them a prominent drug target. Their enzyme activity is tightly spatiotemporally regulated by expression in the precursor form with little or no activity, followed by activation via autoprocessing. These cleavage events are frequently triggered upon transportation to a specific compartment inside the host cell. Typically, precursor oligomerization or the presence of a co-factor is needed for activation. A detailed understanding of these mechanisms will allow ligands with non-canonical mechanisms of action to be designed, which would specifically modulate the initial irreversible steps of viral protease autoactivation. Binding sites exclusive to the precursor, including binding sites beyond the protease domain, can be exploited. Both inhibition and up-regulation of the proteolytic activity of viral proteases can be detrimental for the virus. All these possibilities are discussed using examples of medically relevant viruses including herpesviruses, adenoviruses, retroviruses, picornaviruses, caliciviruses, togaviruses, flaviviruses, and coronaviruses.

scholarly journals Plumbagin and oridonin reveal new CRM1 binding sites and NES-binding groove features

2020 ◽  
Author(s):  
Yuqin Lei ◽  
Yuling Li ◽  
Yuping Tan ◽  
Da Jia ◽  
Qingxiang Sun
Keyword(s):  
Binding Sites ◽  
Nuclear Export ◽  
Drug Target ◽  
Structural Basis ◽  
Inhibitor Binding ◽  
Anti Cancer ◽  
Binding Groove ◽  
First Time ◽  
Further Development ◽  
Important Drug

AbstractCRM1 is an important drug target in diseases such as cancer and viral infection. Plumbagin and oridonin, the herbal ingredients with known anti-cancer activities, were reported to inhibit CRM1-mediated nuclear export. However, their modes of CRM1 inhibition are unclear. Here, a multi-mutant of yeast CRM1 was engineered to enable the crystallization of these two small molecules in CRM1’s NES-binding groove. Each structure showed three inhibitor-binding sites, among which two are conserved in humans. Besides the known binding site, another site also participated in oridonin and plumbagin’s CRM1 inhibition. While the plumbagin-bound NES groove resembled the NES-bound groove state, the oridonin-bound groove revealed for the first time a more open NES groove, which may potentially improve cargo-loading through a capture-and-tighten mechanism. Our work thus provides a tool for CRM1 inhibitor crystallization, new insights of CRM1-cargo interaction, and a structural basis for further development of these or other CRM1 inhibitors.

Predicting the Strength of Stacking Interactions Between Heterocycles and Aromatic Amino Acid Side Chains

2019 ◽  
Author(s):  
Andrea N. Bootsma ◽  
Analise C. Doney ◽  
Steven Wheeler
Keyword(s):  
Amino Acid ◽  
Binding Sites ◽  
Aromatic Amino Acid ◽  
Aromatic Amino Acids ◽  
Biologically Active ◽  
Side Chains ◽  
Stacking Interactions ◽  
Inhibitor Binding ◽  
Protein Binding Sites ◽  
Amino Acid Side Chains

<p>Despite the ubiquity of stacking interactions between heterocycles and aromatic amino acids in biological systems, our ability to predict their strength, even qualitatively, is limited. Based on rigorous <i>ab initio</i> data, we have devised a simple predictive model of the strength of stacking interactions between heterocycles commonly found in biologically active molecules and the amino acid side chains Phe, Tyr, and Trp. This model provides rapid predictions of the stacking ability of a given heterocycle based on readily-computed heterocycle descriptors. We show that the values of these descriptors, and therefore the strength of stacking interactions with aromatic amino acid side chains, follow simple predictable trends and can be modulated by changing the number and distribution of heteroatoms within the heterocycle. This provides a simple conceptual model for understanding stacking interactions in protein binding sites and optimizing inhibitor binding in drug design.</p>

scholarly journals Location of Inhibitor Binding Sites in the Human Inducible Prostaglandin E Synthase, MPGES1

Biochemistry ◽  
2011 ◽  
Vol 50 (35) ◽  
pp. 7684-7693 ◽  
Author(s):  
Edward B. Prage ◽  
Sven-Christian Pawelzik ◽  
Laura S. Busenlehner ◽  
Kwangho Kim ◽  
Ralf Morgenstern ◽  
...  
Keyword(s):  
Binding Sites ◽  
Prostaglandin E ◽  
Inhibitor Binding ◽  
Prostaglandin E Synthase

scholarly journals Structural basis for human TRPC5 channel inhibition by two distinct inhibitors

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Kangcheng Song ◽  
Miao Wei ◽  
Wenjun Guo ◽  
Li Quan ◽  
Yunlu Kang ◽  
...  
Keyword(s):  
Anxiety Disorder ◽  
Binding Sites ◽  
Structural Basis ◽  
Inhibitory Mechanism ◽  
Inhibitor Binding ◽  
Design And Optimization ◽  
Physiological Processes ◽  
Channel Inhibition ◽  
Binding Pockets ◽  
Extracellular Side

TRPC5 channel is a non-selective cation channel that participates diverse physiological processes. TRPC5 inhibitors show promise in the treatment of anxiety disorder, depression and kidney disease. However, the binding sites and inhibitory mechanism of TRPC5 inhibitors remain elusive. Here we present the cryo-EM structures of human TRPC5 in complex with two distinct inhibitors, namely clemizole and HC-070, to the resolution of 2.7 Å. The structures reveal that clemizole binds inside the voltage sensor-like domain of each subunit. In contrast, HC-070 is wedged between adjacent subunits and replaces the glycerol group of a putative DAG molecule near the extracellular side. Moreover, we found mutations in the inhibitor binding pockets altered the potency of inhibitors. These structures suggest that both clemizole and HC-070 exert the inhibitory functions by stabilizing the ion channel in a non-conductive closed state. These results pave the way for further design and optimization of inhibitors targeting human TRPC5.

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