Insight on the interaction between the scorpion toxin blocker Discrepin on potassium voltage-gated channel Kv4.3 by molecular dynamics simulations.

Discrepin is a 38-residue α-toxin extracted from the venom of the Venezuelan scorpion Tityus discrepans, which inhibits ionic transit in the voltage-dependent potassium channels (Kv) of A-type current. The effect of specific residues on the IC50 between Discrepine and Kv4.3, the main component of A-type currents, is known; however, the molecular details of the toxin-channel interaction are not known. In this work, we present interaction models between Discrepin (wt) and two peptide variants (V6K/D20K and K13A) on the pore-forming domain of the Kv4.3 channel obtained from homology, docking, and molecular dynamics modeling techniques. The free energy calculations in these models correspond to the order of the experimentally determined IC50 values. Our studies shed light on the role of the K13 residue as responsible for occluding the Kv4.3 selectivity filter and the importance of the V6K mutation in the approach and stabilization of toxin-channel complex interactions.Communicated by Ramaswamy H. Sarma.

Imidazole and nitroimidazole derivatives as NADH-fumarate reductase inhibitors: Density functional theory studies, homology modeling, and molecular docking.

Chagas disease is caused by Trypanosoma cruzi. Benznidazole and nifurtimox are drugs used for its therapy; nevertheless, they have collateral effects. NADH-fumarate (FUM) reductase is a potential pharmacological target since it is essential for survival of parasite and is not found in humans. The objectives are to design and characterize the electronic structure of imidazole and nitroimidazole derivatives at DFT-M06-2X level in aqueous solution; also, to model the NADH-FUM reductase and analyze its intermolecular interactions by molecular docking. Quantum-chemical descriptors allowed to select the molecules with the best physicochemical properties and lowest toxicity. A high-quality three-dimensional structure of NADH-FUM reductase was obtained by homology modeling. Water molecules do not have influence in the interaction between FUM and NADH-FUM reductase. The main hydrogen-binding interactions for FUM were identified in NADH, Lys172, and Arg89; while hydrophobic interactions in Phe479, Thr174, Met63. The molecules S3-8, S2-8, and S1-8 could be inhibitors of NADH-FUM reductase.

Insights into the Molecular Inhibition of the Oncogenic Channel KV10.1 by Globular Toxins.

Inhibition of the expression of the human ether-à-go-go (hEAG1 or hKV10.1) channel is associated with a dramatic reduction in the growth of several cancerous tumors. The modulation of this channel's activity is a promising target for the development of new anticancer drugs. Although some small molecules have shown inhibitory activity against KV10.1, their lack of specificity has prevented their use in humans. In vitro studies have recently identified a limited number of peptide toxins with proven specificity in their hKV10.1 channel inhibitory effect. These peptide toxins have become desirable candidates to use as lead compounds to design more potent and specific hKV10.1 inhibitors. However, the currently available studies lack the atomic resolution needed to characterize the molecular features that favor their binding to hKV10.1. In this work, we present the first attempt to locate the possible hKV10.1 binding sites of the animal peptide toxins APETx4, Aa1a, Ap1a, and k-hefutoxin 1, all of which described as hKV10.1 inhibitors. Our studies incorporated homology modeling to construct a robust three-dimensional (3D) model of hKV10.1, applied protein docking, and multiscale molecular dynamics techniques to reveal in atomic resolution the toxin-channel interactions. Our approach suggests that some peptide toxins bind in the outer vestibule surrounding the pore of hKV10.1; it also identified the channel residues Met397 and Asp398 as possible anchors that stabilize the binding of the evaluated toxins. Finally, a description of the possible mechanism for inhibition and gating is presented.

Virtual screening of ABCC1 transporter nucleotidebinding domains as a therapeutic target in multidrug resistant cancer.

UNLABELLED: ABCC1 is a member of the ATP-binding Cassette super family of transporters, actively effluxes xenobiotics from cells. Clinically, ABCC1 expression is linked to cancer multidrug resistance. Substrate efflux is energised by ATP binding and hydrolysis at the nucleotide-binding domains (NBDs) and inhibition of these events may help combat drug resistance. The aim of this study is to identify potential inhibitors of ABCC1 through virtual screening of National Cancer Institute (NCI) compounds. A threedimensional model of ABCC1 NBD2 was generated using MODELLER whilst the X-ray crystal structure of ABCC1 NBD1 was retrieved from the Protein Data Bank. A pharmacophore hypothesis was generated based on flavonoids known to bind at the NBDs using PHASE, and used to screen the NCI database. GLIDE was employed in molecular docking studies for all hit compounds identified by pharmacophore screening. The best potential inhibitors were identified as compounds possessing predicted binding affinities greater than ATP. Approximately 5% (13/265) of the hit compounds possessed lower docking scores than ATP in ABCC1 NBD1 (NSC93033, NSC662377, NSC319661, NSC333748, NSC683893, NSC226639, NSC94231, NSC55979, NSC169121, NSC166574, NSC73380, NSC127738, NSC115534), whereas approximately 7% (7/104) of docked NCI compounds were predicted to possess lower docking scores than ATP in ABCC1 NBD2 (NSC91789, NSC529483, NSC211168, NSC318214, NSC116519, NSC372332, NSC526974). Analyses of docking orientations revealed P-loop residues of each NBD and the aromatic amino acids Trp653 (NBD1) and Tyr1302 (NBD2) were key in interacting with high-affinity compounds. On the basis of docked orientation and docking score the compounds identified may be potential inhibitors of ABCC1 and require further pharmacological analysis. ABBREVIATIONS: ABC - ATP-binding cassette, DHS - dehydrosilybin, MDR - multidrug resistance, NBD - nucleotide-binding domain, PDB - protein data bank.

Identification of putative steroid-binding sites in human ABCB1 and ABCG2.

Homology modelling was used to generate three-dimensional structures of the nucleotide-binding domains (NBDs) of human ABCB1 and ABCG2. Interactions between a series of steroidal ligands and transporter NBDs were investigated using an in silico docking approach. C-terminal ABCB1 NBD (ABCB1 NBD2) was predicted to bind steroids within a cavity formed partly by the P-Loop, Tyr1044 and Ile1050. The P-Loop within ABCG2 NBD was also predicted to be involved in steroid binding. No overlap between ATP- and RU-486-binding sites was predicted in either NBD, though overlaps between ATP- and steroid-binding sites were predicted in the vicinity of the P-Loop in both nucleotide-binding domains.