Algorithm to design inhibitors using stereochemically mixed l,d polypeptides: Validation against HIV protease.
Polypeptides have potential to be designed as drugs or inhibitors against the desired targets. In polypeptides, every chiral α-amino acid has enantiomeric structural possibility to become l or d amino acids and can be used as design monomer. Among the various possibilities, use of stereochemistry as a design tool has potential to determine both functional specificity and metabolic stability of the designed polypeptides. The polypeptides with mixed l,d amino acids are a class of peptidomimitics, an attractive drug like molecules and also less susceptible to proteolytic activities. Therefore in this study, a three step algorithm is proposed to design the polypeptides against desired drug targets. For this, all possible configurational isomers of mixed l,d polyleucine (Ac-Leu8-NHMe) structure were randomly modeled with simulated annealing molecular dynamics and the resultant library of discrete folds were scored against HIV protease as a model target. The best scored folds of mixed l,d structures were inverse optimized for sequences in situ and the resultant sequences as inhibitors were validated for conformational integrity using molecular dynamics. This study presents and validates an algorithm to design polypeptides of mixed l,d structures as drugs/inhibitors by inverse fitting them as molecular ligands against desired target.
Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400076, India. Electronic address: poojagupta.135@gmail.com.
Pooja
P
Gupta
Department of Chemistry, Indian Institute of Technology Bombay, Mumbai 400076, India.
Susheel
S
Durani
D000465:Algorithms; D000595:Amino Acid Sequence; D015195:Drug Design; D016333:HIV Protease / Q000737:chemistry / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006860:Hydrogen Bonding; D008024:Ligands; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D017510:Protein Folding; D013237:Stereoisomerism
D017320:HIV Protease Inhibitors; D008024:Ligands; D010455:Peptides; D016333:HIV Protease
De novo design; HIV proteases; Heterochiral folds; Inverse sequence design; Molecular dynamics; Simulated annealing