Introduction: Translesion synthesis (TLS) is a DNA damage tolerance mechanism that replaces the replicative DNA polymerase with a specialized, low-fidelity TLS DNA polymerase that can copy past DNA lesions during active replication. Recent studies have demonstrated a primary role for TLS in replicating past DNA lesions induced by first-line genotoxic agents, resulting in decreased efficacy and acquired chemoresistance. With this in mind, targeting TLS as a combination strategy with first-line genotoxic agents has emerged as a promising approach to develop a new class of anti-cancer adjuvant agents. Areas covered: In this review, we provide a brief background on TLS and its role in cancer. We also discuss the identification and development of inhibitors that target various TLS DNA polymerases or key protein-protein interactions (PPIs) in the TLS machinery. Expert opinion: TLS inhibitors have demonstrated initial promise; however, their continued study is essential to more fully understand the clinical potential of this emerging class of anti-cancer chemotherapeutics. It will be important to determine whether a specific protein involved in TLS is an optimal target. In addition, an expanded understanding of what current genotoxic chemotherapies synergize with TLS inhibitors will guide the clinical strategies for devising combination therapies.

In the present work microwave radiation has been used to prepare the 1 : 1 and 2 : 1 co-crystals of caffeine and maleic acid. We obtained 1 : 1 co-crystals in the presence of water and methanol and we also see Form II of the 1 : 1 co-crystal in methanol. Co-crystallisation under microwave irradiation is shown to be controlled by the saturation of solvent at the reacting interface between the co-crystal components as well as the solvent dielectric properties.

Using integrated in-silico computational techniques, including homology modeling, structure-based and pharmacophore-based virtual screening, molecular dynamic simulations, per-residue energy decomposition analysis and atom-based 3D-QSAR analysis, we proposed ten novel compounds as potential CCR5-dependent HIV-1 entry inhibitors. Via validated docking calculations, binding free energies revealed that novel leads demonstrated better binding affinities with CCR5 compared to maraviroc, an FDA-approved HIV-1 entry inhibitor and in clinical use. Per-residue interaction energy decomposition analysis on the averaged MD structure showed that hydrophobic active residues Trp86, Tyr89 and Tyr108 contributed the most to inhibitor binding. The validated 3D-QSAR model showed a high cross-validated r_cv² value of 0.84 using three principal components and non-cross-validated r² value of 0.941. It was also revealed that almost all compounds in the test set and training set yielded a good predicted value. Information gained from this study could shed light on the activity of a new series of lead compounds as potential HIV entry inhibitors and serve as a powerful tool in the drug design and development machinery.