Effect of HIV-1 Subtype C integrase mutations implied using molecular modeling and docking data.
The degree of sequence variation in HIV-1 integrase genes among infected patients and their impact on clinical response to Anti retroviral therapy (ART) is of interest. Therefore, we collected plasma samples from 161 HIV-1 infected individuals for subsequent integrase gene amplification (1087 bp). Thus, 102 complete integrase gene sequences identified as HIV-1 subtype-C was assembled. This sequence data was further used for sequence analysis and multiple sequence alignment (MSA) to assess position specific frequency of mutations within pol gene among infected individuals. We also used biophysical geometric optimization technique based molecular modeling and docking (Schrodinger suite) methods to infer differential function caused by position specific sequence mutations towards improved inhibitor selection. We thus identified accessory mutations (usually reduce susceptibility) leading to the resistance of some known integrase inhibitors in 14% of sequences in this data set. The Stanford HIV-1 drug resistance database provided complementary information on integrase resistance mutations to deduce molecular basis for such observation. Modeling and docking analysis show reduced binding by mutants for known compounds. The predicted binding values further reduced for models with combination of mutations among subtype C clinical strains. Thus, the molecular basis implied for the consequence of mutations in different variants of integrase genes of HIV-1 subtype C clinical strains from South India is reported. This data finds utility in the design, modification and development of a representative yet an improved inhibitor for HIV-1 integrase.
Departments of Clinical Virology Alagappa University, Karaikudi, Tamil Nadu, India.
Jaiprasath
J
Sachithanandham
SNHRC Vellore and Computer-Aided Drug Design and Molecular Modeling Lab, Department of Bioinformatics Alagappa University, Karaikudi, Tamil Nadu, India.
Karnati
K
Konda Reddy
Departments of Clinical Virology Alagappa University, Karaikudi, Tamil Nadu, India.
King
K
Solomon
Departments of Clinical Virology Alagappa University, Karaikudi, Tamil Nadu, India.
Shoba
S
David
SNHRC Vellore and Computer-Aided Drug Design and Molecular Modeling Lab, Department of Bioinformatics Alagappa University, Karaikudi, Tamil Nadu, India.
Sanjeev
S
Kumar Singh
Departments of Clinical Virology Alagappa University, Karaikudi, Tamil Nadu, India.
Veena
V
Vadhini Ramalingam
Departments of Dermatology, Alagappa University, Karaikudi, Tamil Nadu, India.
Susanne
S
Alexander Pulimood
Departments of Internal Medicine, Alagappa University, Karaikudi, Tamil Nadu, India.
Ooriyapadickal
O
Cherian Abraham
Departments of Internal Medicine, Alagappa University, Karaikudi, Tamil Nadu, India.
Pricilla
P
Rupali
Christian Medical College, Vellore, Sri Sakthi Amma Institute of Biomedical Research Institute.
Gopalan
G
Sridharan
Departments of Clinical Virology Alagappa University, Karaikudi, Tamil Nadu, India.
Rajesh
R
Kannangai
HIV-1; docking and binding energy; dolutegravir; elvitegravir; integrase; modeling; raltegravir