Gita Subba Rao

Structure‐Based Design of a Novel Class of Potent Inhibitors of InhA, the Enoyl Acyl Carrier Protein Reductase from Mycobacterium Tuberculosis: A Computer Modelling Approach

The NADH‐dependent Enoyl‐ACP reductase (InhA) of Mycobacterium tuberculosis has been shown to be the primary target of the frontline drug isoniazid (INH). However, INH must be first activated by katG gene, mutations in which have mediated resistance to INH. Recently, direct inhibitors of InhA have been reported. Using a structure‐based approach, we have identified a tripeptide inhibitor with the sequence WYW, which is 100 times more potent than the existing inhibitors. It is therefore, a potential lead compound for the development of new anti‐TB drugs.

Calculation of the minimum energy conformation of biomolecules using a global optimization technique I. Methodology and application to a model molecular fragment (Normal pentane)

Abstract The conformational energy of a molecule is minimized with respect to interatomic distances using Bremermanns method of unconstrained global optimization (1970). The optimal set of distances is then used for calculating the preferred conformation of the molecule. A simultaneous optimization of all the dihedral angles is achieved. The classical potential function is used in this study. An illustration of the method is given by applying it to normal pentane, which is a commonly occurring fragment of biomolecules. Results show that, for the standard geometry (bond lengths and bond angles), the all-trans) conformation is the preferred one. However, fluctuations of the geometry within the limits of the vibrational spectra can lead to preferred conformations that are not necessarily all-trans.

A mathematical model for insulin kinetics. III. Sensitivity analysis of the model.

A non-linear mathematical model involving four variables and several constants incorporating beta-cell kinetics, a glucose-insulin feedback system and a gastrointestinal absorption term had been applied in earlier papers to various forms of diabetes mellitus. In this paper, we examine the response of the system to variations in the parameters and to initial conditions using sensitivity analysis. It is found that such a method leads to results that are consistent with clinical findings. Further, it is suggested that such an analysis could help in making some predictions regarding future directions in the therapy of diabetes mellitus.

In Silico Structure-Based Design of a Potent and Selective Small Peptide Inhibitor of Protein Tyrosine Phosphatase 1B, A Novel Therapeutic Target for Obesity and Type 2 Diabetes Mellitus: A Computer Modeling Approach

Abstract Protein Tyrosine Phosphatase 1B (PTP1B) has been shown to be a negative regulator of insulin signaling by dephosphorylating key tyrosine residues within the regulatory domain of the β-subunit of the insulin receptor. Recent gene knockout studies in mice have shown the mice to have increased insulin sensitivity and improved glucose tolerance. Furthermore, these mice also exhibited a resistance to diet induced obesity. Inhibitors of PTP1B would have the potential of enhancing insulin action by prolonging the phosphorylated state of the insulin receptor. In addition, recent clinical studies have shown that the haplotype ACTTCAG0 of the PTPN1 gene, which encodes PTP1B, is a major risk contributor to type 2 diabetes mellitus (T2DM). Thus, there is compelling evidence that small molecule inhibitors of PTP1B may be effective in treating insulin resistance at an early stage, thereby leading to a prevention strategy for T2DM and obesity. Based on the crystal structure of the complex of PTP1B with a known inhibitor, we have identified a tetrapeptide inhibitor with the sequence WKPD. Docking calculations indicate that this peptide is as potent as the existing inhibitors. Moreover, the peptide is also found to be selective for PTP1B with a greatly reduced potency against other biologically important protein tyrosine phosphatases such as PTP-LAR, Calcineurin, and the highly homologous T-Cell Protein Tyrosine Phosphatase (TCPTP). Thus the designed tetrapeptide is a suitable lead compound for the development of new drugs against type 2 diabetes and obesity.

The information content of DNA and evolution.

The information content of DNA molecules has been calculated for various organisms using experimentally measured codon frequencies as well as those estimated theoretically. A direct relationship between the information content and the evolutionary rank of the organism is observed. The biological and physical significance of information content in the context of evolution is discussed.

Significance of the information content of DNA in mutations and evolution

Abstract One point mutations in human haemoglobins have been analysed and it is seen that most of these mutations satisfy the condition P 1 > P 2 , where P 1 is the probability of occurrence of the codon that mutates and PZ is that of the codon it mutates to. Further, it is shown that the hypothesis that the information content of DNA is a reasonable evolutionary measure is consistent with the above condition.

A mathematical model for insulin kinetics II. Extension of the model to include response to oral glucose administration and application to insulin-dependent diabetes mellitus (IDDM)

A generalized nonlinear mathematical model which incorporates beta-cell kinetics, a glucose-insulin feedback system and a gastrointestinal absorption term for glucose, is presented. Numerical simulations using this model lead to time variations of plasma glucose and insulin levels that are consistent with clinical observations in normal groups. The results obtained after suitable reduction in some of the parameters are in agreement with the clinical profile and laboratory data in insulin-dependent diabetes mellitus (IDDM). Linear stability analysis of the equations shows that there is a change in the nature of the stability in the transition from the normal case to IDDM, and it is the decrease in the beta cell function which causes this change.

A mathematical model for insulin kinetics and its application to protein-deficient (malnutrition-related) diabetes mellitus (PDDM)

A nonlinear mathematical model which incorporates both beta-cell kinetics and a glucose-insulin feedback system is proposed for describing the time variations of plasma glucose and insulin levels. Numerical simulations show that this model is consistent with experimental observations on normal groups. An analysis of the changes in the solutions with variations in the parameters showed that a decrease in a single parameter gave results consistent with experimental findings in protein-deficient (malnutrition-related) diabetes mellitus (PDDM). The model predicts that it is the function and not the number of beta cells which is reduced in PDDM.

Structure-based design of a novel peptide inhibitor of HIV-1 integrase: a computer modeling approach.

Abstract The insertion of viral DNA into the host chromosome is an essential step in the replication of HIV-1, and is carried out by an enzyme, HIV-1 integrase (IN). Since the latter has no human cellular counterpart, it is an attractive target for antiviral drug design. Several IN inhibitors having activities in the micromolar range have been reported to date. However, no clinically useful inhibitors have yet been developed. Recently reported diketo acids represent a novel and selective class of IN inhibitors. These are the only class which appear to selectively target integrase and two of the inhibitors, L-708,906 and L-731,988, are the most potent inhibitors of preintegration complexes described to date.

Calculation of the minimum energy conformation of biomolecules using a global optimization technique II. Conformation of N-acetylglycine N-methyl amide, a model dipeptide unit

Abstract Further to our study of molecular fragments, the preferred conformation of N -acetylglycine N -methyl amide is calculated by the global optimization method proposed earlier (Subba Rao, Tyagi & Mishra,1981). The classical potential function is used in this study. The results obtained agree with the classical energy calculations of other workers. This study also provides a further test of the efficacy of the method.