Search for new therapeutics against HIV-1 via dual inhibition of RNase H and integrase: Current status and future challenges

Reverse transcriptase and integrase are key enzymes that play a pivotal role in HIV-1 viral maturation and replication. Reverse transcriptase consists of two active sites: RNA-dependent DNA polymerase and RNase H. The catalytic domains of integrase and RNase H share striking similarity, comprising two aspartates and one glutamate residue, also known as the catalytic DDE triad, and a Mg2+ pair. The simultaneous inhibition of reverse transcriptase and integrase can be a rational drug discovery approach for combating the emerging drug resistance problem. In the present review, the dual inhibition of RNase H and integrase is systematically discussed, including rationality of design, journey of development, advancement and future perspective

Molecular docking and dynamics identify potential drugs to be repurposed as SARS-CoV-2 inhibitors

The novel coronavirus disease 19 (COVID-19) has resulted in an estimated 20 million excess deaths and the recent resurgence of COVID-19 in China is predicted to result in up to 1 million deaths over the next few months. With vaccines being ineffective in the case of immunocompromised patients, it is important to continue our quest for safe, effective and affordable drugs that will be available to all countries. Drug repurposing is one of the strategies being explored in this context. Recently, out of the 7817 drugs approved worldwide, 214 candidates were systematically down-selected using a combination of 11 filters including FDA/TGA approval status, assay data against SARS-CoV-2, pharmacokinetic, pharmacodynamic and toxicity profiles. These down-selected drugs were subjected in this study to virtual screening against various SARS-CoV-2 targets followed by molecular dynamics studies of the best scoring ligands against each target. The chosen molecular targets were spike receptor binding domain, nucleocapsid protein RNA binding domain and key nonstructural proteins 3, 5 and 12–14. Four drugs approved for other indications — alendronate, cromolyn, natamycin and treprostinil — look sufficiently promising from our in-silico studies to warrant further in-vitro and in-vivo investigations as appropriate to ascertain their extent of antiviral activities

Synthesis, study of antileishmanial and antitrypanosomal activity of imidazo pyridine fused triazole analogues

KVGCS and SM thank DBT, New Delhi [BT/IN/Spain/39/SMl2017-18] for providing financial support. The financial assistance provided by DIST FIST grant (SR/FST/CSI-240/2012), New Delhi is gratefully acknowledged. SS thanks CSIR for providing SRF fellowship.Four groups, thirty-five compounds in total, of novel 1,2,3-triazole analogues of imidazo-[1,2-a]-pyridine-3-carboxamides were designed and synthesized using substituted pyridine, propargyl bromide, 2-azidoethyl 4-methyl benzenesulfonate and substituted acetylenes. These compounds were characterized using 1H NMR, 13C NMR, LCMS and elemental analyses and a crystal structure was obtained for one of the significantly active compounds, 8f. All the synthesized and characterized compounds were screened in vitro for antileishmanial and antitrypanosomal activity against Leishmania major and Trypanosoma brucei parasites, respectively. Among the tested analogues, fivecompounds (8d, 8f, 8j, 10b and 10d) exhibited significant antileishmanial activity while three compounds (10b, 11a and 11b) showed substantial activity against T. brucei parasite. In silico ADME prediction studies depicted that the essential compounds obeyed Lipinski's rule of five. The predicted in silico toxicity profile suggested that the tested compounds would be non-toxic, which was confirmed experimentally by the lack of cytotoxicity against HeLa cells. Finally, a molecular docking study was also performed, for 10d the most active antileishmanial compound, to study its putative binding pattern at the active site of the selected leishmanial trypanothione reductase target.Publisher PDFPeer reviewe