AIMTo report the preliminary result of the HIV inhibitor screening based on cheminformatics tools and the traditional Chinese medicine database.

METHODSDatabase search was carried out with saquinavir molecule as a template, further screening was made with docking. Detailed studies using molecular dynamics simulation of 50 ps and 200 ps were made with respect to a potential leading compound, leucovorin.

RESULTSThe leucovorin molecule distinguished from other molecules as a potential drug candidate and is subject to extensive studies. The bonding profile and energy were calculated with MD simulations.

CONCLUSIONOur results could be very helpful when we modify leucovorin or design new inhibitors against HIV.

Anti-HIV Agents ; chemistry ; Databases, Factual ; Drug Design ; Drug Evaluation, Preclinical ; methods ; HIV Protease ; chemistry ; HIV Protease Inhibitors ; chemistry ; Leucovorin ; chemistry ; Ligands ; Medicine, Chinese Traditional ; Models, Molecular ; Molecular Conformation ; Saquinavir ; chemistry

OBJECTIVEThe study intended to investigate the effect and mechanism of endoplasmic reticulum stress on cisplatin resistance in ovarian carcinoma.

METHODSRT-PCR and Western blot were used to test the expression of mTOR and Beclin1 mRNA and protein in ovarian cancer SKOV3 cells after saquinavir induction. MTT assay was used to analyze the influence of saquinavir on cisplatin sensitivity in SKOV3 cells.

RESULTSThe IC50 of SKOV3 cells was (5.490 ± 1.148) µg/ml. After induced by Saquinavair 10 µmol/L and 20 µmol/L, the IC50 of SKOV3 cells was increased to (11.199 ± 0.984) µg/ml and (14.906 ± 2.015) µg/ml, respectively. It suggested that the sensitivity of ovarian cancer cells to cisplatin was decreased significantly (P = 0.001). The expression of mTOR and Beclin1 mRNA and protein was significantly different among the five groups: the (Saquinavair+DDP) group of, Saquinavair group, LY294002 group, DDP group and control group (P < 0.001) . The expressions of mTOR and Beclin1 mRNA were highest in the (Saquinavair+DDP) group, 0.684 ± 0.072 and 0.647 ± 0.047, respectively; Secondly, the Saquinavair group, 0.577 ± 0.016 and 0.565 ± 0.037, respectively. The expressions of mTOR and Beclin1 proteins were also highest in the (Saquinavair+DDP) group, 0.624 ± 0.058 and 0.924 ± 0.033, respectively, followed by the Saquinavair group, 0.544 ± 0.019 and 0.712 ± 0.024. 3-MA inhibited the autophagy and restored cisplatin sensitivity in the SKOV3 cells after Saquinavir induced ER stress (P < 0.001).

CONCLUSIONSSaquinavir can effectively induce endoplasmic reticulum stress in SKOV3 cells. Endoplasmic reticulum stress can decrease the sensitivity to cisplatin in SKOV3 cells. The mechanism of the decrease of sensitivity to cisplatin in SKOV3 cells may be that ERS regulates cell autophagy through the mTOR and Beclin1 pathways. ERS of tumor cells and autophagy may become a new target to improve the therapeutic effect of chemotherapy and to reverse the drug resistance in tumor treatment.

Antineoplastic Agents ; pharmacology ; Apoptosis Regulatory Proteins ; genetics ; metabolism ; Autophagy ; drug effects ; Beclin-1 ; Cell Line, Tumor ; Cisplatin ; pharmacology ; Cystadenocarcinoma, Serous ; metabolism ; pathology ; Drug Resistance, Neoplasm ; Endoplasmic Reticulum Stress ; drug effects ; Female ; HIV Protease Inhibitors ; pharmacology ; Humans ; Membrane Proteins ; genetics ; metabolism ; Ovarian Neoplasms ; metabolism ; pathology ; RNA, Messenger ; Saquinavir ; pharmacology ; TOR Serine-Threonine Kinases ; genetics ; metabolism

4-Hydroxycoumarins ; chemical synthesis ; chemistry ; pharmacology ; Anti-HIV Agents ; chemical synthesis ; chemistry ; pharmacology ; Atazanavir Sulfate ; HIV Protease Inhibitors ; chemical synthesis ; chemistry ; pharmacology ; Humans ; Molecular Structure ; Oligopeptides ; chemical synthesis ; chemistry ; pharmacology ; Pyridines ; chemical synthesis ; chemistry ; pharmacology ; Saquinavir ; chemical synthesis ; chemistry ; pharmacology ; Urea ; analogs & derivatives ; chemical synthesis ; chemistry ; pharmacology

In the two decades since AZT was first approved for clinical use in 1987, 24 additional antiretroviral agents have been approved. They include 7 nucleoside analogs, a nucleotide analog and 4 non-nucleoside reverse transcriptase inhibitors, 10 protease inhibitors, 2 entry inhibitors and an integrase inhibitor. More than 20 investigational agents are currently being studied in clinical trials. Highly active antiretroviral therapy (HAART), which involves a combination of anti-HIV-1 drugs, is extremely effective in suppressing HIV-1 replication and increasing CD4+ number and results in substantial reductions in HIV-1-related morbidity and mortality. In last 20 years, much has been learned about resistance to antiretroviral drugs, drug interactions and metabolic complications of antiviral drug use. Drugs are now selected on the basis of resistance tests and on the risk of specific drug complications in individual patients. As a result, decisions about the therapy of HIV/AIDS have become personalized and are made on a patient-by-patient basis. With appropriate medical management, a person with HIV-1 now has the possibility of a nearly normal life expectancy.
Anti-HIV Agents ; adverse effects ; pharmacology ; therapeutic use ; Antiretroviral Therapy, Highly Active ; Cyclohexanes ; chemistry ; pharmacology ; therapeutic use ; Drug Resistance, Viral ; HIV Envelope Protein gp41 ; chemistry ; therapeutic use ; HIV Fusion Inhibitors ; chemistry ; pharmacology ; therapeutic use ; HIV Infections ; drug therapy ; HIV Integrase Inhibitors ; chemistry ; pharmacology ; therapeutic use ; HIV Protease Inhibitors ; chemistry ; pharmacology ; therapeutic use ; HIV Reverse Transcriptase ; chemistry ; pharmacology ; therapeutic use ; HIV-1 ; drug effects ; physiology ; Humans ; Molecular Structure ; Peptide Fragments ; chemistry ; therapeutic use ; Pyrrolidinones ; chemistry ; pharmacology ; therapeutic use ; Raltegravir Potassium ; Saquinavir ; chemistry ; pharmacology ; therapeutic use ; Triazoles ; chemistry ; pharmacology ; therapeutic use ; Virus Replication ; drug effects ; Zidovudine ; chemistry ; pharmacology ; therapeutic use