Reactions of Ru(III)-drugs KP1019 and KP418 with guanine, 2'-deoxyguanosine and guanosine: a DFT study.

Ruthenium (Ru)-based anticancer drugs are considered to be novel alternatives of platinum-based drugs. They exhibit potent cytotoxicity against the cancer cells and hence are useful for the treatment of cancer. Herein, the density functional theory calculations in the gas phase and aqueous media are carried out to study the reactions of two Ru(III)-based drugs such as KP1019 and KP418 with the N7 site of guanine (G), 2'-deoxyguanosine (dGua), and guanosine (Gua) to understand their reactivity against the DNA and RNA. All the reactions are found to be exothermic. The activation free energies and rate constants of these reactions indicate that KP1019 and KP418 would react with the dGua more readily than Gua. Hence, the binding of these drugs with the DNA would be more preferred as compared to RNA. It is further found that among these drugs, KP1019 would be more reactive than KP418 in agreement with the experimental observation. Thus, this study is expected to aid in the future development of potent anticancer drugs.

C-Terminal Extended Hexapeptides as Potent Inhibitors of the NS2B-NS3 Protease of the ZIKA Virus.

The Zika virus (ZIKV) protease is an attractive drug target for the design of novel inhibitors to control the ZIKV infection. As the protease substrate-binding site contains acidic residues, inhibitors with basic residues can be beneficial for the inhibition of protease activities. Molecular dynamics (MD) simulation and molecular mechanics with generalized Born and surface area solvation (MM/GBSA) techniques are employed herein to design potent peptide inhibitors and to understand the nature of the basic residues that can potentially stabilize the acidic residues of the protease substrate-binding site. It is found that the inclusion of K, R, and K at P1, P2, and P3 positions, respectively, and Y at the P4 position (YKRK) would generate a highly stable tetrapeptide-protease complex with a ΔGbind of ~ -80 kcal/mol. We have also shown that the C-terminal extension of this and the second most stable tetrapeptide (YRRR) with small polar residues, such as S and T would generate even more stable hexapeptide-protease complexes. The modes of interactions of these inhibitors are discussed in detail, which are in agreement with earlier experimental studies. Thus, this study is expected to aid in the design of novel antiviral drugs against the ZIKV.

Does tautomerization of FapyG influence its mutagenicity?

Oxidative degradation of guanine to 2,6-diamino-4-oxo-5-formamidopyrimidine (FapyG) is believed to be mutagenic. It has been proposed recently that the enol tautomer of FapyG is mainly responsible for this effect leading to a guanine-to-thymine mutation (T. H. Gehrke, U. Lischke, K. L. Gasteiger, S. Schneider, S. Arnold, H. C. Muller, D. S. Stephenson, H. Zipse, T. Carell, Nat. Chem. Biol.- 2013, 9, 455-461). Here, density functional methods suggest that the enol tautomer of FapyG might not be responsible for the proposed guanine-to-thymine mutation. Instead, it might result in a guanine-to-adenine mutation.

Binding of BIS like and other ligands with the GSK-3ß kinase: a combined docking and MM-PBSA study.

Binding of several bisindolylmaleimide (BIS) like (BIS-3, BIS-8 and UCN1) and other ligands (H89, SB203580 and Y27632) with the glycogen synthase kinase-3 (GSK-3ß) has been studied using combined docking, molecular dynamics and Poisson-Boltzmann surface area analysis approaches. The study generated novel binding modes of these ligands that can rationalize why some ligands inhibit GSK-3ß while others do not. The relative binding free energies associated with these binding modes are in agreement with the corresponding measured specificities. This study further provides useful insight regarding possible existence of multiple conformations of some ligands like H89 and BIS-8. It is also found that binding modes of BIS-3, BIS-8 and UCN1 with GSK-3ß and PDK1 kinases are similar. These new insights are expected to be useful for future rational design of novel, more potent GSK-3ß-specific inhibitors as promising therapeutics.

A theoretical study of some new analogues of the anti-cancer drug camptothecin.

The enzyme topoisomerase I (topo I), which is essential for cell replication, transiently causes a DNA single strand break and makes a complex with it. The anti-cancer agent camptothecin (CPT) binds to the topo I-DNA complex and stabilizes it, preventing resealing of the broken DNA strand and cell growth. Considering the structural factors of CPT that are believed to be involved in stabilizing the topo I-DNA complex via hydrogen bonding and stacking interactions, designs of two new analogues of CPT (topo I inhibitors) have been suggested. The molecular geometries of CPT, two of its analogues and certain other related molecules included in the study were fully optimized in both gas phase and aqueous media at the B3LYP/6-311++G(d,p) level of density functional theory. Solvation effects of aqueous media were treated using the polarizable continuum model (PCM). Net CHelpG charges and surface molecular electrostatic potentials (MEP) near the atomic sites of the molecules were studied. Structural analogy and surface MEP values suggests that the two new CPT analogues studied here would be potent topoisomerase I inhibitors.