Structural investigation of 2‐naphthyl phenyl ether inhibitors bound to WT and Y181C reverse transcriptase highlights key features of the NNRTI binding site

Abstract

Human immunodeficiency virus (HIV)‐1 remains as a global health issue that is primarily treated with highly active antiretroviral therapy, a combination of drugs that target the viral life cycle. One class of these drugs are non‐nucleoside reverse transcriptase inhibitors (NNRTIs) that target the viral reverse transcriptase (RT). First generation NNRTIs were troubled with poor pharmacological properties and drug resistance, incentivizing the development of improved compounds. One class of developed compounds are the 2‐naphthyl phenyl ethers, showing promising efficacy against the Y181C RT mutation. Further biochemical and structural work demonstrated differences in potency against the Y181C mutation and binding mode of the compounds. This work aims to understand the relationship between the binding mode and ability to overcome drug resistance using macromolecular x‐ray crystallography. Comparison of 2‐naphthyl phenyl ethers bound to Y181C RT reveal that compounds that interact with the invariant W229 are more capable of retaining efficacy against the resistance mutation. Additional modifications to these compounds at the 4‐position, computationally designed to compensate for the Y181C mutation, do not demonstrate improved potency. Ultimately, we highlight important considerations for the development of future HIV‐1 drugs that are able to combat drug resistance.

Exploring novel HIV‐1 reverse transcriptase inhibitors with drug‐resistant mutants: A double mutant surprise

“…Although both Compounds 2a and 2b also shift downward in the V106A/ Y181C double mutant, the tryptophan residue rotates down into the pocket to maintain an optimal interaction distance. A similar dependence of potency against mutant strains on W229 interaction strength has also been observed in the related 2-naphthyl diether series (Duong et al, 2020).…”

Rational design of allosteric modulators: Challenges and successes

“…[317][318][319][320] In a computer-aided NNRTI design journey that nearly lasted 20 years, 321 lead generation using de novo design with the BOMB 322 software, virtual screening with Glide, 26,[228][229][230] and lead optimization with free energy perturbation (FEP) calculations combined with MC with the MCPRO 323 program led to the discovery of NNRTIs and their optimization from micromolar to picomolar concentrations, the most potent NNRTIs reported to date. [324][325][326][327][328][329][330] This computational procedure of lead generation and optimization led to the discovery and crystallization of picomolar activity NNRTIs selective for the Y181C and Y181C/K103N HIV-RT mutant proteins. [331][332][333] Flavivirus NS2B-NS3 protease Flavivirus is a genus composed of more than 70 viruses causing severe and deadly diseases.…”

“…HIV‐RT possesses a unique and highly selective hydrophobic allosteric pocket in which many diverse allosteric inhibitors called non‐nucleoside reverse transcriptase inhibitors (NNRTIs) have been designed, six of them now being FDA‐approved 317–320 . In a computer‐aided NNRTI design journey that nearly lasted 20 years, 321 lead generation using de novo design with the BOMB 322 software, virtual screening with Glide, 228–231 and lead optimization with free energy perturbation calculations combined with MC with the MCPRO 323 program led to the discovery of NNRTIs and their optimization from micromolar to picomolar concentrations, the most potent NNRTIs reported to date 324–330 . This computational procedure of lead generation and optimization also led to the discovery and crystallization of picomolar activity NNRTIs selective for the Y181C and Y181C/K103N HIV‐RT mutant proteins 331–333 …”