Non-nucleoside reverse transcriptase inhibitors (NNRTI) has a definitive role and most commonly used in treatment of HIV infection. NNRTI act by binding to specific binding site (non-nucleoside binding pocket-NNBP) in reverse transcriptase (RT) enzyme. With the objective of developing efficient NNRTI, we have designed various Isatin analogs for effective treatment of AIDS and were subjected to molecular docking studies on five different crystal structures of RT complexed with five different ligands Nevirapine, Delaviridine, Efavirenz, Etravirine, and Rilpivirine. Combined dock-score of compound N21, N11, N23 was found to be comparable with standards indicated that Isatin analogs have good binding affinity for NNBP. Docking results suggested that these types of compounds could be binding in the NNRTI binding site in a similar mode to a known non-nucleoside inhibitors. ADME properties of Isatin analogs were also analyzed using Qikprop 2.5 tool of Schrodinger software.
Validation of CMT (GeneXpert; Cepheid Diagnostics; Sunnyvale, CA) for MTI and RR is difficult given scarcity of positive patient specimens. Simulated patient samples containing MT, M gordonae (MG) and M avium complex (MAC) were constructed from ATCC Mycobacterium (MB) cell lines (CLs) 25177, 14470 and 15769 (Manassas, VA) and killed RR (x2) and wild type (WT) cellular controls (MMQC; Scarborough, ME). Five blank patient samples were pooled, diluted with sterile saline, cultured (x2), tested with the CMT (x2) and at reference lab [RL] (Lab Corp; Burlington, NC) with consistently (-) results. MBCLs were added to blank sputum to a concentration of 50 CFU/mL and the MMQC controls to a concentration of 50 cells/mL. In subsequent studies MBCL simulated samples were concentrated, stained and cultured using standard techniques and the BacT/Alert system (Biomerieux; Durham, NC). PCR were compared between CMT and RL. Simulated MAC (x3) and MG (x2) specimens were smear (+) but only MAC was culture (+). All were CMT and RL (-).The first simulated MT specimen revealed rare (1+) organisms on smear and was RL (-)/CMT (+); whereas the second was smear (-), RL (equivocal)/CMT (-). Both were culture (-). Three additional simulated MT specimens were smear, culture, RL and CMT (+). Samples using RR and WT control cells were RL "equivocal" and (-) respectively but all CMT (+). The CMT correctly identified RR in the control material. Controls were run once a day for 20 consecutive days and gave expected results for both MTI and RR. External source material with known properties can "fill in" for scarce patient samples but additional sources of variation are introduced including shipping and handling, variability in specimen preparation and learning curve effects. Such considerations may explain the MG culture failure and MT result variability.
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