Positional Adaptability in the Design of Mutation-Resistant Nonnucleoside HIV-1 Reverse Transcriptase Inhibitors: A Supramolecular Perspective

Abstract

Drug resistance is a key cause of failed treatment of HIV infection. The efficacy of nonnucleoside reverse transcriptase-inhibiting (NNRTI) drugs is impaired by the rapid emergence of drug-resistant mutations. The literature supports the idea that purposefully designed flexible NNRTIs at an active site may help overcome drug resistance. It is proposed here that the usual ''lock and key'' model, with respect to NNRTI drug design, be expanded to consider creating ''master keys'' that would automatically adjust conformations to fit all of the ''locks'' mutations may make. The present work introduces the novel perspective of designing and creating supramolecular assemblies as potential NNRTIs (instead of the relatively more rigid single-molecule inhibitors). Specifically, flexible self-assembling quinhydrone supramolecular dimers formed from quinonoid monomers (designed to be highly flexible NNRTIs themselves) will be offered as a working example of this new perspective in NNRTI drug design. Quinonoid compounds have demonstrated binding interactions at various sites of the HIV-1 RT enzyme, including the elusive ribonuclease H area. Quinhydrone self-organized dimers have at some point in their molecular architecture a noncovalently interacting donor-acceptor ring pair complex. This complex is at the heart of the increased torsional, rotational, and translational motion this species will experience at a particular active site. Flexible supramolecular assemblies, together with their flexible monomer components, may offer a critical advantage in retaining potency against a wide range of drug-resistant HIV-1 RTs. This new supramolecular perspective may also have broader implications in the general field of antimicrobial drug design.

Antiviral activity of natural humic substances and shilajit materials against HIV-1: Relation to structure

“…Humic substances (HS) have been known for a long time for their antiviral activity ( Helbig et al 1997 , Klöcking et al, 2002 ). The different fractions of natural HS and synthetic HS-like materials are active against HIV ( Botes et al 2002 , Brucolleri et al 2013 , Kornilaeva et al 2019 , Zhernov et al 2017 , Zhernov, 2018 ), influenza virus A/WSN/1933 (H1N1) ( Lu et al, 2002 ), herpes simplex virus-1 (HSV-1) ( Klöcking et al, 2002 ), Coxsackie virus A9 ( Klöcking et al, 1972 ), tick-borne encephalitis virus (TBEV) ( Orlov et al, 2019 ).…”

Supramolecular combinations of humic polyanions as potent microbicides with polymodal anti-HIV-activities

“…Despite these numerous findings, systematic studies on HS fractions from a drug-design perspective are very scarce. 40 This is because, until recently, the arsenal of chemists was lacking the tools required for the identification of molecular compositions of complex supramolecular systems. This situation has changed with the advent of Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS) which has an unprecedented resolution capacity.…”

Benefits of multidimensional fractionation for the study and characterization of natural organic matter

“…Moreover, humics and "humic-mimetics" (synthetically made HULIS) are studied for their antiviral, antibacterial, and cancer-related properties. [12][13][14] In short, against the backdrop of a rising global population with increasing needs for food/high-yield agricultural soil, safe drinking water, new pharmaceuticals, fuel, clean air and climate normalization, the ability to characterize structure-activity relationship of NOM would constitute an enormous advancement.…”