How Does a Drug Molecule Find Its Target Binding Site?

Shan, Yibing; Kim, Eric T.; Eastwood, Michael P.; Dror, Ron O.; Seeliger, Markus A.; Shaw, David E.

doi:10.1021/ja202726y

Cited by 600 publications

(716 citation statements)

References 11 publications

Supporting

Mentioning

678

Contrasting

Unclassified

Order By: Relevance

“…This result provides a picture different from that provided by standard protein−drug interaction. 61 While, on average, the contact surface between a small-molecule ligand and its protein receptor is 300−1000 Å 2 , 62 we find that the average contact surface of NQTrp with Aβ42, calculated using all conformations, is only 259 ± 7.4 Å 2 (with a minimum of 68 Å 2 and a maximum of 396 Å 2 ). Taken together, our results indicate that there is room to design more efficient drugs targeting Aβ42 dimer against AD.…”

Section: ■ Conclusionmentioning

confidence: 81%

Atomic and Dynamic Insights into the Beneficial Effect of the 1,4-Naphthoquinon-2-yl-l-tryptophan Inhibitor on Alzheimer’s Aβ1–42 Dimer in Terms of Aggregation and Toxicity

Zhang

et al. 2013

ACS Chem. Neurosci.

View full text Add to dashboard Cite

Aggregation of the amyloid β protein (Aβ) peptide with 40 or 42 residues is one key feature in Alzheimer's disease (AD). The 1,4-naphthoquinon-2-yl-L-tryptophan (NQTrp) molecule was reported to alter Aβ self-assembly and reduce toxicity. Though nuclear magnetic resonance experiments and various simulations provided atomic information about the interaction of NQTrp with Aβ peptides spanning the regions of residues 12−28 and 17−42, none of these studies were conducted on the fulllength Aβ1−42 peptide. To this end, we performed extensive atomistic replica exchange molecular dynamics simulations of Aβ1−42 dimer with two NQTrp molecules in explicit solvent, by using a force field known to fold diverse proteins correctly. The interactions between NQTrp and Aβ1−42, which change the Aβ interface by reducing most of the intermolecular contacts, are found to be very dynamic and multiple, leading to many transient binding sites. The most favorable binding residues are Arg5, Asp7, Tyr10, His13, Lys16, Lys18, Phe19/Phe20, and Leu34/Met35, providing therefore a completely different picture from in vitro and in silico experiments with NQTrp with shorter Aβ fragments. Importantly, the 10 hot residues that we identified explain the beneficial effect of NQTrp in reducing both the level of Aβ1−42 aggregation and toxicity. Our results also indicate that there is room to design more efficient drugs targeting Aβ1−42 dimer against AD.

show abstract

Section: ■ Conclusionmentioning

confidence: 81%

Atomic and Dynamic Insights into the Beneficial Effect of the 1,4-Naphthoquinon-2-yl-l-tryptophan Inhibitor on Alzheimer’s Aβ1–42 Dimer in Terms of Aggregation and Toxicity

Zhang

et al. 2013

ACS Chem. Neurosci.

View full text Add to dashboard Cite

show abstract

“…PKA belongs to the AGC family of kinases, which are typically characterized by a cis-regulatory C-terminal tail (20). Recently multiple-microsecond timescale simulations have been performed on several tyrosine kinases (21)(22)(23)(24), and a Markov model was constructed for activation of Src kinase that Significance Protein kinases represent a critically important family of regulatory enzymes. Their activity can be altered by mutations and binding events distant from the active site.…”

mentioning

confidence: 99%

Dynamic architecture of a protein kinase

McClendon

Kornev

Gilson

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

234

273

View full text Add to dashboard Cite

To better understand the mechanism of long distance allosteric signaling inside the protein kinase core using protein kinase A (PKA) as a prototype, we obtained 5μs molecular dynamics trajectories in different liganded and conformational states using the Anton supercomputer, providing for the first time an opportunity to observe intermediate‐timescale conformational transitions in the study of the dynamics of this stable kinase. We used community analysis to identify structurally‐contiguous groups of residues exhibiting correlated motions in the kinase catalytic domain. This dynamic partitioning of the kinase into communities provides a framework for analyzing the local vs. long‐range effects of mutations, binding, phosphorylation, etc. We hypothesize that perturbations will be readily felt within these communities and then propagated possibly to a lesser extent to other elements through correlated motions. Moreover, using a wealth of published mutational data, we can annotate these communities with functions. Our functional annotation of kinase communities provides an extremely valuable framework for viewing a signaling enzyme in terms of functional substructures rather than isolated linear motifs such as secondary structure elements and short three or four residue motifs. Figure 1. Functional annotation of the kinase communitiy map. Each community is shown in red on the structure of PKA. Grant Funding Source: Supported by NIH F32 GM099197, R01 GM19301

show abstract

“…2 [28] incorporated into the Schrödinger suite 9.3 [29]. Each simulation was carried out for 5 nanoseconds (ns).…”

Section: Molecular Dynamicsmentioning

confidence: 99%

Pyrazole Based Inhibitors against Enzymes of Staphylococcus aureus: A Computational Study

Jagadeesan¹,

Vijayakuma

Palayam

et al. 2015

J Proteomics Bioinform

View full text Add to dashboard Cite

How Does a Drug Molecule Find Its Target Binding Site?

Cited by 600 publications

References 11 publications

Atomic and Dynamic Insights into the Beneficial Effect of the 1,4-Naphthoquinon-2-yl-l-tryptophan Inhibitor on Alzheimer’s Aβ1–42 Dimer in Terms of Aggregation and Toxicity

Atomic and Dynamic Insights into the Beneficial Effect of the 1,4-Naphthoquinon-2-yl-l-tryptophan Inhibitor on Alzheimer’s Aβ1–42 Dimer in Terms of Aggregation and Toxicity

Dynamic architecture of a protein kinase

Pyrazole Based Inhibitors against Enzymes of Staphylococcus aureus: A Computational Study

Contact Info

Product

Resources

About