title: Structural basis of drug resistance by genetic variants of HIV type 1 clade c protease from India.
abstract: Using computer modeling of three-dimensional structures and structural information available on the crystal structures of HIV-1 protease, we investigated the structural effects of mutations, in treatment-naive and treatment-exposed individuals from India and postulated mechanisms of resistance in clade C variants. A large number of models (14) have been generated by computational mutation of the available crystal structures of drug bound proteases. Localized energy minimization was carried out in and around the sites of mutation in order to optimize the geometry of interactions present. Most of the mutations result in structural differences at the flap that favors the semiopen state of the enzyme. Some of the mutations were also found to confer resistance by affecting the geometry of the active site. The E35D mutation affects the flap structure in clade B strains and E35N and E35K mutation, seen in our modeled strains, have a more profound effect. Common polymorphisms at positions 36 and 63 in clade C also affected flap structure. Apart from a few other residues Gln-58, Asn-83, Asn-88, and Gln-92 and their interactions are important for the transition from the closed to the open state. Development of protease inhibitors by structure-based design requires investigation of mechanisms operative for clade C to improve the efficacy of therapy.
authors.affiliation: Department of Clinical Virology, Christian Medical College, Vellore, India.
authors.forename: Abraham Joseph
authors.initials: AJ
authors.lastname: Kandathil
authors.forename: Agnel Praveen
authors.initials: AP
authors.lastname: Joseph
authors.forename: Rajesh
authors.initials: R
authors.lastname: Kannangai
authors.forename: Narayanaswamy
authors.initials: N
authors.lastname: Srinivasan
authors.forename: Oriapadickal Cherian
authors.initials: OC
authors.lastname: Abraham
authors.forename: Susanne Alexander
authors.initials: SA
authors.lastname: Pulimood
authors.forename: Gopalan
authors.initials: G
authors.lastname: Sridharan
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics*; D024882:Drug Resistance, Viral; D005838:Genotype; D015658:HIV Infections / Q000821:virology*; D016333:HIV Protease / Q000737:chemistry / Q000235:genetics*; D015497:HIV-1 / Q000737:chemistry / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D007194:India; D008958:Models, Molecular; D020125:Mutation, Missense; D011110:Polymorphism, Genetic; D017434:Protein Structure, Tertiary
chemical_list: D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1