Supplementary Information Drug discovery strategies in the design and development of non-nucleoside reverse transcriptase inhibitors (NNRTIs)

AIDS (acquired immunodeficiency syndrome) is potentially a life-threatening infectious disease caused by human immunodeficiency virus (HIV). Till date, thousands of people lose their lives annually due to HIV infection and continues to be a big public health issue globally. Since the discovery of the first drug, Zidovudine (AZT), a nucleoside reverse transcriptase inhibitor (NRTI), till date, 30 drugs have been approved by FDA primarily targeting reverse transcriptase, integrase and/or protease enzymes. The majority of these drugs target the catalytic and allosteric sites of the HIV enzyme reverse transcriptase. Compared to the NRTI family of drugs, the diverse chemical class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) has special anti-HIV activity with high specificity and low toxicity. However, current clinical usage of NRTI and NNRTI drugs has limited therapeutic value due to their adverse drug reactions and the emergence of multidrug-resistant (MDR) strains. To overcome drug resistance and efficacy issues, combination therapy is widely prescribed for HIV patients. Combination antiretroviral therapy (cART) include more than one antiretroviral agents targeting two or more enzymes in the life cycle of the virus. Medicinal chemistry researchers apply different optimization strategies including structure- and fragment-based drug design, prodrug approach, scaffold hopping, molecular/fragment hybridization, and bioisosterism to identify and develop novel NNRTIs with high antiviral activity against wild-type (WT) and mutant strains. The formulation experts design various delivery systems with single or combination therapy and long-acting regimens of NNRTI to improve pharmacokinetic profiles and sustained therapeutic effects