Despite the introduction of HAART therapy, the need for new anti-HIV agents is still very high because the current medicines do not provide complete curation of HIV infection, exhibit severe side effects, and lead to the emergence of resistant virus strains. A recent new project at the NCI's CADD Group, called the Synthetically Accessible Virtual Inventory (SAVI), has opened up new possibilities for discovery of novel anti-HIV agents from previously unexploited parts of chemical space. To select the most promising hits among the 283 million SAVI molecules generated so far, one needs computational methods for analysis of this big data chemical-biological space. We are applying the computer program PASS Affinity to the SAVI database for this purpose. PASS (Prediction of Activity Spectra for Substances), developed at the Institute of Biomedical Chemistry, predicts more than 7,000 kinds of biological activity with an average accuracy of about 95% based on structure-activity relationships derived from a training set comprising about 1 million drug-like molecules. We have additionally created new computational methods for assessing similarity based on MNA (Multilevel Neighborhoods of Atoms) and QNA (Quantitative Neighborhoods of Atoms) chemical descriptors, and PBAS (Predicted Biological Activity Spectra) biological descriptors. To validate the methods, we collected a set of 36 anti-HIV small-molecule anti-HIV drugs (28 launched drugs and 8 in phase III clinical trials). Four validated molecular mechanisms of antiretroviral action broadly describe this set's biological space: HIV-1 reverse transcriptase, HIV-1 protease, HIV-1 integrase and HIV-1 attachment inhibitors. We obtained high accuracy of prediction via similarity based on the MNA, QNA, and PBAS descriptors. Still, PASS Affinity provided yet better accuracy of prediction compared to the similarity assessments (Sensitivity = 0.89; Specificity = 0.96; Precision = 0.72; Balanced Accuracy = 0.97). We discuss the results of exploratory analyses of the SAVI database, to reveal its pharmacological potential for treatment and prophylactics of HIV/AIDS.

Chemical-biological space exploration for discovery of novel anti-HIV agents

254th National Meeting (2017)

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