Identification of HIV Inhibitors Guided by Free Energy Perturbation Calculations

Abstract

Free energy perturbation (FEP) theory coupled to molecular dynamics (MD) or Monte Carlo (MC) statistical mechanics offers a theoretically precise method for determining the free energy differences of related biological inhibitors. Traditionally requiring extensive computational resources and expertise, it is only recently that its impact is being felt in drug discovery. A review of computer-aided anti-HIV efforts employing FEP calculations is provided here that describes early and recent successes in the design of human immunodeficiency virus type 1 (HIV-1) protease and non-nucleoside reverse transcriptase inhibitors. In addition, our ongoing work developing and optimizing leads for small molecule inhibitors of cyclophilin A (CypA) is highlighted as an update on the current capabilities of the field. CypA has been shown to aid HIV-1 replication by catalyzing the cis/trans isomerization of a conserved Gly-Pro motif in the Nterminal 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.

Role of Molecular Dynamics and Related Methods in Drug Discovery

“…145 Other successful examples include inhibitors of the tautomerase activity of human macrophage migration inhibitory factor (MIF) 146−148 and others. 149 Taken together, these paradigmatic examples attest the impact of FEP calculations on lead optimization for drug discovery, with a clear demonstration that this approach, nowadays, offers great advantages and progress.…”

Quantum and molecular mechanical Monte Carlo techniques for modeling condensed‐phase reactions

“…Accurate calculation of free energy changes is essential for the characterization of chemical processes. Recent reviews on the FEP calculations and historical perspectives are available . FEP uses the Zwanzig expression (Eq. )…”

Computational perspective and evaluation of plausible catalytic mechanisms of peptidyl-prolyl cis–trans isomerases

“…[6]Development of new classes of FKBP inhibitors may, therefore, serve as treatment for neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases.A detailed understanding of the catalytic mechanism of FKBPs and other PPIases and their molecular interactions will assist and advance the design of new classes of inhibitors. [13,[16][17][18][19][20] One of the earlieststudies of the catalytic mechanism of FKBP by Fischer et al, using computational modeling, showed that a peptide (N-acetyl-Leu-Pro-Phe-methylamide) substrate analogue interacted with FKBP by adopting a type VIaproline turn conformation. [11]A combination of hydrophobic and hydrogen bonding interactions were responsible for the favorable free energy of FKBP-substrate complex formation.…”