A virtual library of constrained cyclic tetrapeptides that mimics all four side-chain orientations for over half the reverse turns in the protein data bank

Abstract

Reverse turns are often recognition sites for protein/protein interactions and, therefore, valuable potential targets for determining recognition motifs in development of potential therapeutics. A virtual combinatorial library of cyclic tetrapeptides (CTPs) was generated and the bonds in the low-energy structures were overlapped with canonical reverse-turn Calpha-Cbeta bonds (Tran et al., J Comput Aided Mol Des 19(8):551-566, 2005) to determine the utility of CTPs as reverse-turn peptidomimetics. All reverse turns in the Protein Data Bank (PDB) with a crystal structures resolution < or = 3.0 A were classified into the same known canonical reverse-turn Calpha-Cbeta bond clusters (Tran et al., J Comput Aided Mol Des 19(8):551-566, 2005). CTP reverse-turn mimics were compiled that mimicked both the relative orientations of three of the four as well as all four Calpha-Cbeta bonds in the reverse turns of the PDB. 54% of reverse turns represented in the PDB had eight or more CTPs structures that mimicked the orientation of all four of the Calpha-Cbeta bonds in the reverse turn.

Limiting Assumptions in the Design of Peptidomimetics

“…On the other hand, constrained mimetics allow precise determination of the bound conformation of the ligand that facilitates scaffold hopping. Criteria for mimicry can impact the success as well; simple overlap of carbon‐α positions [Whitby et al, ] on which to attach amino‐acid sidechains is not as restrained as requiring correct orientation of the α‐β vectors [Tran et al, ; Arbor and Marshall, ], nor access to the correct torsional values of the α‐β vector [Che et al, ] for orientation of the rest of the sidechain to mimic the surface of the receptor‐bound conformation of the parent peptide. As our design criteria and methodologies evolve to realistically generate organic peptidomimetics that mimic the interactive surface of the ligand, one can expect design to replace approximation and focused combinatorial chemistry to find the best mimetic.…”

“…Based on concepts first implemented by the Bartlett group with CAVEAT [Lauri and Bartlett, ; Yang et al, ], the topological orientation of amino acid sidechains (CαCβ vectors) to characterize reverse turns was stressed by Tran et al [] rather that the classical definition by backbone torsional angles by Venkatachalam [], or the set of distances between backbone α‐carbons [Whitby et al, ]. The Tran classification scheme was used by Arbor and Marshall to characterize the ability of cyclic tetrapeptides (CTPs) to act as scaffolds for orientation of the four sidechains as seen in the diverse set of reverse turns found in the PDB [Arbor and Marshall, ]. CTPs containing proline and N ‐Me‐amino acids with alternating chirality of the amino acids are highly constrained (Fig.…”

“…Both the Smythe [Horton et al, 2002a[Horton et al, ,2002b[Horton et al, , 2008 and Marshall [Che and Marshall, 2006a;Arbor et al, 2008;Arbor and Marshall, 2009] groups have advocated CTPs as probes of receptor recognition and demonstrated synthetic accessibility as well as conformational semirigidity. Based on the bioactivity exerted by the cyclodepsipeptide largazole [Taori et al, 2008], a potent class I lysine deacetylase (KDAC) inhibitor, Reddy et al, have recently investigated the use heteroproline dipeptide reverseturn mimetics (based on Pro-D-pro and D-pro-Pro dipeptide combinations) for the development of isoform-specific lysine deacetylases inhibitors (KDA-CIs) as simplified largazole analogs [Reddy et al, 2016] (Fig.…”

Antitumor and Antimicrobial Activity of Some Cyclic Tetrapeptides and Tripeptides Derived from Marine Bacteria

“…Many of these host-defense peptides (HDPs) are also anticancer peptides (ACPs) with potent abilities to inhibit the growth of a wide range of cancer cells [ 3 , 4 , 5 , 6 ]. Although the antimicrobial activity of peptides can now be predicted [ 7 , 8 ], the potency of these antimicrobial peptides is normally not as strong as certain conventional antibiotics. Their major strengths are broad-spectrum abilities to kill multi-drug-resistant bacteria at similar concentrations, rapid bacterial activity, and low propensity for resistance [ 9 , 10 ].…”

CycloPs: Generating Virtual Libraries of Cyclized and Constrained Peptides Including Nonnatural Amino Acids

“…Constrained peptides may act as peptidomimetics of natural, linear peptides, 1,2 and may make more suitable therapeutic candidates, as the conformational constraint has been seen to increase specificity to a protein target, 3 as well as provide protection from proteolytic degradation. 4 The advantages that constrained peptides display over linear peptides have led to their use as potential protein binding compounds in phage-display libraries, 5 as mimics of protein turn structure in virtual libraries, 6 and as binding ligands of RNA in virtual libraries. 7 To generate virtual libraries of constrained peptides, it is necessary to use chemoinformatics techniques to assemble the amino acid building blocks into a linear peptide.…”