Three significant points should be emphasized: 1) immunosuppressive and anti-viral effects of CsA are possibly independent [161, 162], 2) inhibition of cyclophilin is a potentially useful strategy for reducing HIV-1 infectivity and replication and isomerization of the – Gly-Pro- angle in Ace-His-Ala-Gly-Pro-Ile-Ala-Nme . Gly-Pro motif in the N-terminal domain of HIV-1 capsid (CA) protein. In the absence of a functional CypA, e.g., by the addition of an inhibitor such as cyclosporine A (CsA), HIV-1 has reduced infectivity. Our simulations of acylurea-based and 1-indanylketone-based CypA inhibitors have determined that their nanomolar and micromolar binding affinities, respectively, are tied to their ability to stabilize Arg55 and Asn102. A structurally novel 1-(2,6-dichlorobenzamido) indole core was proposed to maximize these interactions. FEP-guided optimization, experimental synthesis, and biological testing of lead compounds for toxicity and inhibition of wild-type HIV-1 and CA mutants have demonstrated a dose-dependent inhibition of HIV-1 infection in two cell lines. While the inhibition is modest compared to CsA, the results are encouraging. design of small molecules that Hexachlorophene bind to a biological target in order to inhibit its function has made great advancements in methodology in recent years for multiple computer-aided drug design (CADD) techniques [1C13]. However, medicinal chemists engaged in CADD often find that accurately predicting the binding affinities of potential drugs is an extremely difficult and time consuming task . For example, virtual screening methods, such as docking ligands into a receptor, allow for a large number of compounds to be vetted quickly, but they often neglect important statistical and chemical contributions in favor of computational efficiency . As a result, large quantitative inaccuracies of the Hexachlorophene relative and absolute free energies of binding generally occur . While large and continual advances in computational power have helped to advance the field , additional improvements in algorithms and methods will be necessary if calculations are to become routine and prospective predictions interpreted with confidence [18, 19]. Free energy perturbation (FEP) simulations rooted in statistical mechanics provide an avenue to incorporate missing effects into the calculations, e.g., conformational sampling, explicit solvent, and shift of protonation states upon binding [20C22], but they generally require extensive computational resources and expertise [23C25]. Despite the challenge, FEP simulations for the identification of drug-like scaffolds and subsequent optimization of binding affinities have been successfully reported, such as the recent development of inhibitors for T4 lysozyme mutants [26, 27], fructose-1,6-bisphosphatase [28, 29], and neutrophil elastate . Given the large body of work that is primarily concerned with using free energy calculations to guide structure-based Hexachlorophene drug design this review cannot be exhaustive. Instead a more manageable review of computer-aided efforts to design antiretroviral compounds by employing FEP simulations, including our current work developing leads for small molecule inhibitors targeting cyclophilin A (CypA), will be highlighted. HIV-1 Human immunodeficiency virus type 1 (HIV-1) is the causative agent of acquired immunodeficiency syndrome (AIDS), a disease of pandemic proportions that has killed an estimated 25 million people worldwide and remains one of the leading world-wide causes of infectious disease related deaths . HIV-1 also carries a significant social stigma as many countries lack laws protecting people living with HIV from discrimination . Tragically, it is estimated that 33.3 million people are currently infected with HIV-1 worldwide and approximately 2. 6 million people were newly infected in 2009 2009 . The implementation of multiple drug combinations of highly active antiretroviral therapy (HAART) in 1996 significantly reduced HIV-associated morbidity and mortality. However, by the late 1990s HIV-1 strains exhibiting resistance frequencies as high as 24 % to individual drugs in HAART emerged in urban areas and the prevalence of multidrug-resistant viruses was approximately 10 to 13 % in 2006 [33, 34]. While continued efforts to combat HIV-1 have identified multiple druggable targets , such as the co-receptors CCR5 and CXCR4, Gag protein processing , and integrase , the majority of the 25 approved antiretroviral drugs (as of 2011) by the U.S. Food and Drug Administration (FDA) are directed against two Rabbit Polyclonal to OR2AT4 virally encoded enzymes essential to virus replication: protease and reverse transcriptase [32, 38C40]. Combating HIV-1 Hexachlorophene with CADD The past several years have been witness to many great successes in developing HIV-1 inhibitors with computer-aided approaches, e.g., virtual screening [41C44], molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) [45C47], molecular mechanics generalized Born surface area (MM-GB/SA) [48C50], and linear interaction energy (LIE) [51C53]. However, in keeping with the theme of this review, i.e., free energy perturbation calculations, not all studies can be highlighted. Fortunately, an excellent review by Liang and co-workers provides an extensive review of important achievements over the past five-years in the discovery of HIV-1 inhibitors utilizing CADD methods . The method of interest.